4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines

ABSTRACT

This disclosure describes novel 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines having anti-asthmatic activity.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of our abandoned application Ser. No. 817,951, filed Jan. 13, 1986.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds and, more particularly, is concerned with novel 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines having anti-asthmatic activity which may be represented by the following structural formula: ##STR1## wherein R₁ is hydrogen, alkyl(C₁ -C₃), --COCO₂ C₂ H₅ or N,N-dimethylaminoethyl; R₂ is mono- or poly-substituted phenyl wherein the substituents are alkyl(C₁ -C₆), alkoxy(C₁ -C₃), chloro, bromo, iodo, trifluoromethyl, hydroxy, phenyl, amino, monoalkyl-(C₁ -C₃)amino, dialkyl(C₁ -C₃)amino, alkyl(C₁ -C₃)keto, propenyloxy, carboxyl, oxyacetic acid, oxyacetic acid ethyl ester, sulfamilamido, N,N-dialkyl(C₁ -C₃)sulfamilamido, N-methylpiperazinyl, piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-z-yl, 1-naphthyl, cyclopentyl, 3,4-dimethylbenzyl or moieties of the formula: ##STR2## wherein R is alkyl(C₁ -C₃), X is oxygen (--O--) or sulfur (--S--), m is 1-3, n is 2 or 3, R₆ is hydrogen, alkyl(C₁ -C₃), alkoxy (C₁ -C₃), chloro, bromo, iodo or trifluoromethyl, R₇ is 1H-imidazol-1-yl or morpholino and R₈ is alkyl(C₁ -C₃), phenyl or monosubstituted phenyl wherein the substituents are alkyl(C₁ -C₃), halogen or trifluoromethyl; R₃ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, 2-furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, 2-benzofuranyl, 2-(pyridine-N-oxide), 3-(pyridine-N-oxide), 4-(pyridine-N-oxide), 1H-indol-2-yl, 1H-indol-3-yl, 1-methyl-1H-pyrrol-2-yl, 4-quinolinyl, 4-pyri-dinyl methyl iodide, dimethylaminophenyl or N-acetyl-N-methylaminophenyl; R₄ is hydrogen or alkyl(C₁ -C₃); and R₅ is hydrogen or alkyl(C₁ -C₃); and the pharmacologically acceptable acid-addition salts thereof.

The present invention also icludes novel compositions of matter containing the above-defined compounds which are useful for treating asthma, allergic diseases, inflammation and diabetes in mammals. The invention also comprises processes of preparing the compounds within the scope of the above formula.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention are obtainable as crystalline materials having characteristic melting points and absorption spectra. They are in general sparingly soluble in organic solvents such as lower alkanols, chloroform, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, acetone and the like, but are generally insoluble in water.

The novel 4,5,6-substituted-2-pyrimidinamines of the present invention in general may be prepared as set forth in the following reaction schemes. ##STR3## wherein R₁, R₂, R₃, R₄ and R₅ are as hereinabove defined.

In accordance with Scheme I, a heteroaryl (R₃) alkanoyl (R₄) compound 1, e.g 2-acetylpyridine, 2-acetylfuran, 3-acetylthiophene, 2-acetyl-6-methylpyridine, 2-propionyl pyridine or 3-propionyl pyridine and the like, is reacted with a di(lower alkyl)-formamide or acetamide di(lower alkyl) acetal 2, e.g; N,N-dimethylformamide dimethylacetal or N,N-dimethylacetamide dimethylacetal at an elevated temperature in the range of about 50° C. to about 150° C. for from about 4 to 24 hours to produce the 3-di(lower alkyl)aminoacrylophenone 3. The acrylophenone 3 is then reacted with an appropriately substituted phenylguanidine (R₁)(R₂), 4 as the base or as the carbonate, sulfate, nitrate, hydrochloride or dihydrochloride salt in an inert solvent such as absolute ethanol, n-propanol, isopropyl alcohol or 2-methoxyethanol and the like, by heating at the reflux temperature for from 6-48 hours. The product 5 is separated by the partial evaporation of the solvent, then cooling and collected and recrystallized in a conventional manner from solvents such as n-propyl alcohol, isopropyl alcohol, absolute ethyl alcohol or 2-methoxyethanol and the like and combinations of solvents such as chloroform/hexane, dichloromethane/hexane or isopropyl alcohol/ethylene glycol monomethyl ether and the like. ##STR4## wherein R₁, R₂, R₃, R₄ and R₅ are as hereinabove defined.

In accordance with Scheme II, when the 4,5,6-substituted-2-pyrimidinamine product 5 is dissolved by heating in a solvent such as absolute ethanol, isopropyl alcohol or dichloromethane, then stirred at room temperature and reacted with a mineral acid such as sulfuric acid, hydrochloric acid, nitric acid or phosphoric acid and the like, dissolved in absolute ethanol or isopropyl alcohol and the like, the 4,5,6-substituted-2-pyrimidinamine acid addition salt 6 is precipitated on standing for 30 minutes and chilling for several hours.

Alternatively, acid addition salts may be formed with organic acids such as citric acid or maleic acid and the like by dissolving the desired 4,5,6-substituted-2-pyrimidinamine in hot, absolute ethanol or 2-methoxyethanol in the presence of the organic acid. Cooling provides the desired compounds as solids.

The novel compounds of the present invention are highly active as antiasthmatic and antiallergic agents as will be demonstrated hereinbelow.

The bronchospasm of allergic asthma is a consequence of the release of mediators, such as histamine and slow-reacting substances from masts cells. The role of mediator release in the induction of an asthmatic attack has been fully reviewed and documented; see Kaliner, M. and Austen, K. F., Bronchial Asthma Mechanisms and Therepautics, E. B. Weiss, Editor, Little, Brown and Company, Boston, 163, (1976); Lichtenstein, L. M., Asthma-Physiology, Immunopharmacology and Treatment, Second International Symposium, L. M. Lichtenstein and K. F. Austen, Editors, Academic Press, New York, 51, (1979); and Bell, S. C., et al., Annular Reports in Medicinal Chemistry, 14, 51, H. J. Hess, Editor, Academic Press, New York, (1979).

The novel compounds of this invention have been tested by the procedure of Lichtenstein, L. M. and Osler, A. G., J. Exp. Med., 120, 507-530 (1964), which evaluates the ability of compounds to inhibit mediator (histamine) release from immunologically stimulated human basophils.

Reagents

10X Concentrated Tris Buffer

Dissolve 140.3 g of sodium chloride, 7.45 g of Trizma-Tris Pre-Set, Reagent Grade, pH 7.6, at 25° C. (Sigma Chemical Co.) in sufficient water to give a final volume of 2 liters.

Human Albumin

(Sigma Chemical Co.) (30 mg/ml)

Calcium and Magnesium Stocks

Made to 0.075M 0.5M respectively, with calcium chloride dihydrate and magnesium chloride hexahydrate.

Tris-A Buffer

A 10 ml portion of 10X Tris Buffer and 1.0 ml of human albumin are diluted to 100 ml with water.

Tris ACM Buffer

A 10 ml portion of 10X Tris Buffer, 1.0 ml of human albumin, 0.8 ml of calcium stock and 0.2 ml of magnesium stock are diluted to 100 ml with water.

Rabbit Antihuman IgE

Behring Diagnostics (Generally used at 10 μg protein/ml final concentration).

House Dust Mite Extract (Dermatophagoides Farinae)

Strength 1:100 (w:v) allergenic extract, Hollister-Stier Labs. Generally this is diluted 1:1000 to 1:10,000 (considering the vial as stock).

Other Allergens

Interdermal solutions or intramuscular preparations for hyposensitization, Hollister-Steir Labs. The final concentration used is on the order of 1 PNU/ml.

Separation of Leukocytes from Human Blood and Challenge

Eighty millimeters of blood is withdrawn from subjects with known histamine release to anti-IgE, ragweed antigen or other specific allergen, using four 20 ml heparinized tubes. This 80 ml of blood is mixed with 20 ml of saline containing 0.6 g of dextrose and 1.2 g of dextran. The blood is allowed to sediment at room temperature in two 50 ml polycarbonate centrifuge tubes until a sharp interface develops between the red cells and plasma (60-90 minutes). The plasma (top) layer from each tube is withdrawn by pipet and transferred to respective 50 ml polycarbonate tubes. The plasma is centrifuged for 8 minutes at 110X G at 4° C. The supernatant is carefully poured off as completely as possible and the cell button is resuspended in 2-3 ml of Tris-A buffer using a siliconized Pasteur pipet. The resuspension is accomplished by drawing the liquid gently in an out of the pipet, with the tip below the liquid until an even suspension of cells is obtained. Sufficient Tris-A buffer is then added to bring the volume in the tube to about 45 ml and the tube is centrifuged at 110X G for 8 minutes at 4° C. The supernatant is poured off and the cell button is resuspended and centrifuged as described above. The supernatant is poured off and the cell button is suspended in 2-3 ml of Tris-ACM buffer to make the final volume sufficient to allow addition to the reaction tubes.

Reaction tubes containing anti-IgE or antigens, either alone or with test compound in a total volume of 0.2 ml are prepared and placed in a 37° C. bath. The cells are warmed to 37° C. and frequently swirled to ensure an even suspension, while 1.0 ml aliquots are added to each reaction tube. The tubes are then incubated for 60 minutes at 37° C., vortexing the tubes gently every 15 minutes to keep the cells evenly suspended. When the reaction is complete, the tubes are centrifuged at 4° C. for 10 minutes at 1500 rpm to sediment the cells. One ml aliquots of supernatant are transferred to 12 mm by 75 mm polyethylene tubes and 0.2 ml of 8% perchloric acid is added to each tube. Blanks and totals are included in each test. The blanks have cells and all reagents except antigen or anti-IgE. The totals contain 0.24 ml of 8% perchloric acid, one ml of cells and 0.2 ml of buffer. All samples are then centrifuged to remove the precipitate protein.

Assay of Released Histamine by the Automated Fluorometric Method

This automated method has been described by Siraganian, R. P., in Anal. Biochem. 57, 383 (1974) and J. Immunol. Methods, 7, 283 (1975) and is based on the manual method of Shore, P. A., et al., J. Pharmacol. Exp. Ther., 217, 182 (1959).

The automated system consists of the following Technicon Autoanalyzer II components: Sampler IV, Dual-Speed Proportioning Pump III, Fluoronephelometer with a narrow pass primary filter 7-60 and a secondary filter 3-74, Recorder, and Digital Printer. The manifold used is the one described by Siraganian vide supra, with the following modifications: the dialyzer is omitted; all pumping tubes pass through a single proportioning pump with large capacity and twice the volume of sample is taken for analysis.

The automated chemistry consists of the following steps: Extraction from alkaline saline into butanol, back extraction into dilute hydrochloric acid by addition of heptane, reaction of histamine with o-phthaldialdehyde (OPT) at high pH and conversion of the OPT adduct to a stable fluorophore with phosphoric acid. The reaction product is then passed through the fluorometer. The full scale response is adjusted to 50 ng histamine base with a threshold sensitivity of approximately 0.5 ng.

Calculation of the Results of Histamine Release Tests

The instrument blank (wash) is subtracted from the ng histamine of each sample. Then the ng histamine of each sample is divided by the mean of the three totals (cells lysed with perchloric acid) to obtain percent release.

Control samples contain antigen but no test compound. Blank (or spontaneous release) samples contain neither antigen nor test compound. The mean of the blanks (three replicates) is subtracted from the percent release for controls and test compounds.

The means for control and test compound groups are computed and the result for a test compound is computed as percent of control by the formula: ##EQU1##

Values obtained at different concentrations of test compound are used to calculate an IC₅₀ (the concentration in μM which causes a 50% inhibition of histamine release) by linear regression. A compound is considered active if the IC₅₀ is ≦48 μM.

The results of this test on typical compounds of this invention appear in Table I.

                  TABLE I                                                          ______________________________________                                         Inhibition of Histamine Release from                                           Immunologically Stimulated Human Basophils                                     Compound                   IC.sub.50 (μM)                                   ______________________________________                                         4-(2-Furanyl)-5-methyl- .sub.--N--phenyl-2-pyrimidin-                                                     17.7                                                amine                                                                          4-(4-Pyridinyl)- .sub.--N--[(3-trifluoromethyl)phenyl]-                                                   32.0                                                2-pyrimidinamine                                                                .sub.--N--(4-Methoxyphenyl)-4-(3-pyridinyl)-2-                                                           1.4                                                 pyrimidinamine                                                                  .sub.--N--Phenyl-4-(3-pyridinyl)-2-pyrimidinamine                                                        0.9                                                  .sub.--N--(4-Acetylphenyl)-4-(3-pyridinyl)-2-                                                            0.8                                                 pyrimidinamine                                                                  .sub.--N--(4-Fluorophenyl)-4-(3-pyridinyl)-2-                                                            <48                                                 pyrimidinamine                                                                  .sub.--N--(4-Methoxyphenyl)-4-(2-pyridinyl)-2-pyrimi-                                                    8.3                                                 dinamine                                                                        .sub.--N--(4-Methoxyphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                    1.0                                                 dinamine                                                                        .sub.--N--(4-Fluorophenyl)-4-(4-pyridinyl)-2-pyrimi-                                                     1.9                                                 dinamine                                                                        .sub.--N--(4-Bromophenyl)-4-(3-pyridinyl)-2-pyrimi-                                                      2.3                                                 dinamine                                                                       4-(3-Pyridinyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-                                                   0.7                                                 2-pyrimidinamine, hydrochloride                                                4-(2-Pyridinyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-                                                   2.9                                                 2-pyrimidinamine                                                                .sub.--N--(4-Methoxyphenyl)-4-(2-thienyl)-2-pyrimi-                                                      3.9                                                 dinamine                                                                        .sub.--N--(4-Ethylphenyl)-4-(1-methyl-1 .sub.--H--pyrrol-2-                                              <48                                                 yl)-2-pyrimidinamine                                                            .sub.--N--Phenyl-4-(2-thienyl)-2-pyrimidinamine                                                          31.7                                                 .sub.--N--(3-Chloro-4-methylphenyl)-4-(3-pyridinyl)-2-                                                   9.3                                                 pyrimidinamine                                                                  .sub.--N--(3-Methylphenyl)-4-(2-pyridinyl)-2-pyrimi-                                                     0.7                                                 dinamine                                                                        .sub.--N--(3-Methylphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                     9.4                                                 dinamine                                                                         .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine                                                       0.9                                                  .sub.--N--(3-Methylphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                     1.5                                                 dinamine                                                                        .sub.--N--(4-Ethylphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                      7.7                                                 dinamine                                                                        .sub.--N--(4-Ethylphenyl)-5-methyl-4-(4-pyridinyl)-2-                                                    <48                                                 pyrimidinamine                                                                  .sub.--N--(4-Ethylphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                      <48                                                 dinamine                                                                        .sub.--N--(4-Ethylphenyl)-4-(2-pyridinyl)-2-pyrimi-                                                      2.1                                                 dinamine                                                                        .sub.--N--(3-Methylphenyl)-4-(2-thienyl)-2-pyrimi-                                                       0.3                                                 dinamine                                                                       4-(2-Furanyl)- .sub.--N--phenyl-2-pyrimidinamine                                                          48                                                  4-(2-Furanyl)- .sub.--N--(3-methylphenyl)-2-pyrimi-                                                       3.5                                                 dinamine                                                                        .sub.--N--(4-Ethylphenyl)-4-(6-methyl-3-pyridinyl)-2-                                                    13.4                                                pyrimidinamine                                                                  .sub.--N--(4-Ethylphenyl)-6-methyl-4-(6-methyl-3-                                                        19.1                                                pyridinyl)-2-pyrimidinamine                                                     .sub.--N--[4-(4-Methyl-1-piperazinyl)phenyl]-4-(2-                                                       <24                                                 thienyl)-2-pyrimidinamine                                                       .sub.--N--(4-Ethylphenyl)-4-pyrazinyl-2-pyrimidinamine                                                   2.8                                                  .sub.--N--(3-Methylphenyl)-4-pyrazinyl-2-pyrimi-                                                         5.4                                                 dinamine                                                                        .sub.--N--(2-Methylphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                     3.9                                                 dinamine                                                                        .sub.--N--(3-Ethylphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                      10.6                                                dinamine                                                                        .sub.--N--(2,5-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                        47.1                                                pyrimidinamine                                                                  .sub.--N--(2,3-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                        20.2                                                pyrimidinamine                                                                  .sub.--N--(3-Methylphenyl)-4-(3-thienyl)-2-pyrimidin-                                                    3.8                                                 amine                                                                           .sub.--N--(2,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                        <48                                                 pyrimidinamine                                                                  .sub.--N--(3,5-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                        4.4                                                 pyrimidinamine                                                                  .sub.--N--1-Naphthalenyl-4-(4-pyridinyl)-2-pyrimidin-                                                    31.3                                                amine                                                                           .sub.--N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                        1.0                                                 pyrimidinamine                                                                  .sub.--N--1-Naphthalenyl-4-(2-pyridinyl-2-pyrimidin-                                                     3.0                                                 amine                                                                           .sub.--N--(2,4-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                        24.0                                                pyrimidinamine                                                                 4-(4-Pyridinyl)- .sub.--N--(2,4,6-trimethylphenyl)-2-                                                     10.5                                                pyrimidinamine                                                                 4-(2-Furanyl)- .sub.--N--(4-methoxyphenyl)-2-pyrimidin-                                                   <48                                                 amine                                                                           .sub.--N--[4-(4-Methyl-1-piperazinyl)phenyl]-4-(2-                                                       <24                                                 pyridinyl)-2-pyrimidinamine                                                    4-(2-Furanyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-2-                                                   <48                                                 pyrimidinamine                                                                  .sub.--N--(4-Fluorophenyl)-4-(2-furanyl)-2-pyrimidin-                                                    13.3                                                amine                                                                           .sub.--N--Cyclopentyl-4-(2-pyridinyl)-2-pyrimidinamine                                                   2.2                                                  .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                       3.5                                                 compound with 2-hydroxy-1,2,3-propanetricar-                                   boxylate (2:1)                                                                  .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                       1.0                                                 (Z)-2-butenedioate (1:1)                                                        .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                       3.0                                                 sulfate                                                                         .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                       1.2                                                 dinitrate                                                                       .sub.--N--(4-Ethylphenyl)-4-(4-pyridinyl)-2-pyrimidin-                                                   17.7                                                amine, pyridine-1-oxide                                                         .sub.--N--(3,4-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                        5.9                                                 pyrimidinamine                                                                  .sub.--N--(4-Methoxyphenyl)-4-(3-thienyl)-2-pyrimidin-                                                   15.6                                                amine                                                                           .sub.--N--(3-Ethylphenyl)-4-(2-furanyl)-2-pyrimidin-                                                     9.7                                                 amine                                                                          4-(1 .sub.--H--Indol-3-yl)- .sub.--N--phenyl-2-pyrimidinamine                                             3.0                                                  .sub.--N--(2-Methoxy-5-methylphenyl)-4-(4-pyridinyl)-                                                    6.9                                                 2-pyrimidinamine                                                                .sub.--N--(3-Methylphenyl)-4-(1-methyl-1 .sub.-- H--pyrrol-2-                                            9.4                                                 yl)-2-pyrimidinamine                                                            .sub.--N--(3-Ethylphenyl)-4-(2-thienyl)-2-pyrimidin-                                                     48.0                                                amine                                                                           .sub.--N--(3-Ethylphenyl)-4-(3-thienyl)-2-pyrimidin-                                                     1.1                                                 amine                                                                          4-(1 .sub.--H--Indol-2-yl)- .sub.--N--(3-methylphenyl)-2-pyrimi-                                          2.2                                                 dinamine                                                                       4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]-                                                                 27.5                                                benzoic acid, methyl ester                                                      .sub.--N--(3-Methylphenyl)-4-(4-quinolinyl)-2-pyrimi-                                                    10.9                                                dinamine                                                                        .sub.--N--Phenyl-4-(-4-quinolinyl)-2-pyrimidinamine                                                      3.0                                                  .sub.--N--(4-Ethylphenyl)-4-(4-quinolinyl)-2-pyrimi-                                                     4.0                                                 dinamine                                                                       4-(2-Pyridinyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-                                                   3.0                                                 2-pyrimidinamine, sulfate                                                       .sub.--N--(3-Methylphenyl)-4-(2-thienyl)-2-pyrimidin-                                                    3.0                                                 amine, sulfate                                                                 4-(2-Furanyl)- .sub.--N--[3-(methylphenyl)]-2-pyrimi-                                                     3.0                                                 dinamine, sulfate                                                               .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                       3.3                                                 phosphate                                                                       .sub.--N--(3,5-Dimethylphenyl)-4-(2-furanyl)-2-pyrimi-                                                   0.7                                                 dinamine                                                                        .sub.--N--(3,5-Dimethylphenyl)-4-(2-thienyl)-2-pyrimi-                                                   4.3                                                 dinamine                                                                        .sub.--N--(2,4-Difluorophenyl)-4-(4-pridinyl)-2-                                                         <48                                                 pyrimidinamine                                                                  .sub.--N--(2,4-Difluorophenyl)-4-(3-pyridinyl)-2-                                                        <48                                                 pyrimidinamine                                                                  .sub.--N--(3-Methylphenyl)-4-(5-methyl-2-thienyl)-                                                       1.4                                                 2-pyrimidinamine                                                                .sub.--N--(2,6-Difluorophenyl)-4-(4-pyridinyl)-2-                                                        2.9                                                 pyrimidinamine                                                                 4-(4-Pyridinyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-                                                   <48                                                 2-pyrimidinamine, sulfate                                                       .sub.--N--(4-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                    <48                                                 dinamine, sulfate                                                               .sub. --N--Phenyl-4-(3-pyridinyl)-2-pyrimidinamine,                                                      3.0                                                 sulfate                                                                        4-(3-Pyridinyl)- .sub.--N--[3-(trifluoromethyl)phenyl]-                                                   2.6                                                 2-pyrimidinamine, sulfate                                                       .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                       3.0                                                 dihydrochloride                                                                 .sub.--N--[4-(1,1-Dimethylethyl)phenyl]-4-(3-pyridin-                                                    0.7                                                 yl)-2-pyrimidinamine                                                            .sub.--N--(2,6-Difluorophenyl)-4-(3-pyridinyl)-2-                                                        22.0                                                pyrimidinamine                                                                  .sub.--N--(4-Ethylphenyl)-4-(5-methyl-2-thienyl)-2-                                                      36.3                                                pyrimidinamine                                                                  .sub.--N--[(3,4-Dimethylphenyl)methyl]-4-(2-pyridinyl-                                                   39.8                                                2-pyrimidinamine                                                                .sub.--N--(3,5-Dimethylphenyl)-4-(3-pyridinyl)-2-                                                        3.0                                                 pyrimidinamine, sulfate                                                         .sub.--N--(3,5-Dimethylphenyl)-4-(3-pyridinyl)-2-                                                        3.0                                                 pyrimidinamine, phosphate                                                       .sub.--N--(3-Methylphenyl)-4-(1 .sub.--H--pyrrol-2-yl)-2-                                                11.1                                                pyrimidinamine                                                                 4-(5-Methyl-2-furanyl)- .sub.--N--(3-methylphenyl)-2-                                                     2.0                                                 pyrimidinamine                                                                 4-Methyl-6-(5-methyl-2-thienyl)- .sub.--N--phenyl-2-                                                      24.8                                                pyrimidinamine                                                                  .sub.--N--[4-(Dimethylamino)phenyl]-4-(4-pyridinyl)-2-                                                   3.8                                                 pyrimidinamine                                                                  .sub.--N--(3-Methoxyphenyl)-4-(4-pyridinyl)-2-pyrimi-                                                    0.4                                                 dinamine                                                                        .sub.--N--(3-Methoxyphenyl)-4-(2-pyridinyl)-2-pyrimi-                                                    0.2                                                 dinamine                                                                        .sub.--N--[4-(Dimethylamino)phenyl]-4-(2-pyridinyl)-2-                                                   2.7                                                 pyrimidinamine                                                                  .sub.--N--(3-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                    0.3                                                 dinamine                                                                        .sub.--N--(3,5-Dimethylphenyl)-4-(3-pyridinyl)-2-                                                        0.8                                                 pyrimidinamine                                                                 4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                                 12.4                                                benzoic acid, ethyl ester                                                       .sub.--N, .sub.--N--Dimethyl-  .sub.--N'-- [4-(3-pyridinyl)-2-pyrimidin-                                 3.7                                                 yl]-1,4-benzenediamine                                                         4-(2,5-Dimethyl-3-furanyl)- .sub.--N--phenyl-2-pyrimi-                                                    2.0                                                 dinamine                                                                        .sub.--N, .sub.--N--Dimethyl- .sub.--N'-- [4-(4-pyridinyl)-2-pyrimi-                                     0.4                                                 dinyl)benzenediamine, trihydrochloride                                         4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(3-methylphenyl)-                                                   28.5                                                2-pyrimidinamine                                                               4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(3,5-dimethyl-                                                      4.1                                                 phenyl-2-pyrimidinamine                                                         .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidin-                                   4.4                                                 ly]-1,4-benzenediamine, dihydrochloride                                        4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(4-ethylphenyl)-                                                    19.2                                                2-pyrimidinamine                                                                .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-pyridinyl)-2-pyrimi-                                      1.7                                                 dinyl]-1,3-benzenediamine                                                      3-[[4-(2-Pyridinyl)-2-pyrimidinyl]amino]ben-                                                              3.0                                                 zoic acid, ethyl ester                                                          .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidin-                                   0.5                                                 yl]-1,3-benzenediamine                                                         4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenol                                                            5.1                                                 3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]ben-                                                              20.3                                                zoic acid, ethyl ester                                                          .sub.--N--(4-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                    3.2                                                 dinamine, phosphate                                                             .sub.--N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                        0.6                                                 pyrimidinamine, sulfate                                                         .sub. --N--[4-(2-Propenyloxy)phenyl]-4-(3-pyridinyl)-2-                                                  0.8                                                 pyrimidinamine                                                                  .sub.--N--[4-[2-(Dimethylamino)ethoxy]phenyl]-4-                                                         0.5                                                 (3-pyridinyl)-2-pyrimidinamine                                                  .sub.--N--Phenyl-4-(3-pyridinyl)-2-pyrimidinamine,                                                       2.7                                                 phosphate                                                                       .sub.--N'--[4-(2-Furanyl)-2-pyrimidinyl]- .sub.--N, .sub.--N--                                           1.9                                                 dimethyl-1,4-benzenediamine                                                     .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-thienyl)-2-pyrimidinyl]-                                  0.6                                                 1,4-benzendiamine                                                               .sub.--N'--[4-(2,5-Dimethyl-3-furanyl)-2-pyrimidinyl]-                                                   4.9                                                  .sub.--N, .sub.--N--dimethyl-1,4-benzenediamine                                .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-methyl-2-thienyl)-2-                                      1.8                                                 pyrimidinyl]-1,4-benzenediamine                                                 .sub.--N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                        0.3                                                 pyrimidinamine, phosphate                                                       .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-pyridinyl)-2-pyrimidin-                                   1.5                                                 yl]-1,4-benzenediamine, trihydrochloride                                        .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimidin-                                   3.5                                                 yl]-1,3-benzenediamine                                                          .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-methyl-6-(4-pyridinyl)-2-                                    37.7                                                pyrimidinyl]-1,4-benzenediamine                                                 .sub.--N--[4-[3-Dimethylamino)propoxy]phenyl]-4-(3-                                                      0.5                                                 pyridinyl)-2-pyrimidinamine                                                     .sub.--N--[4-[2-Diethylamino)ethoxy]phenyl]-4-(3-                                                        0.2                                                 pyridinyl)-2-pyrimidinamine                                                     .sub.--N--[4-[2-Dimethylamino)ethoxy]phenyl]-4-(3-                                                       0.5                                                 pyridinyl)-2-pyrimidinamine, hydrochloride                                     4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]ben-                                                              7.6                                                 zoic acid                                                                       .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidin-                                   0.5                                                 yl]-1,3-benzenediamine, dihydrochloride                                         .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidin-                                   1.0                                                 yl]-1,3-benzenediamine, trihydrochloride                                        .sub.--N--(3,5-Dimethylphenyl)-4-(2-furanyl)-5-methyl-                                                   <24                                                 2-pyrimidinamine                                                                .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimidin-                                   0.5                                                 yl]-1,3-benzenediamine, dihydrochloride                                         .sub.--N'--[4-(2-Furanyl)-5-methyl-2-pyrimidinyl]- .sub.--N, .sub.--N--                                  6.1                                                 dimethyl-1,4-benzenediamine                                                    4-(2-Furanyl)-5-methyl- .sub.--N--phenyl-2-pyrimidin-                                                     5.0                                                 amine, sulfate                                                                  .sub.--N'--[4-(2-Benzofuranyl)-2-pyrimidinyl]- .sub.--N, .sub.--N--di-                                   5.6                                                 methyl-1,4-benzenediamine                                                      4-Methyl- .sub.--N--phenyl-6-(2-pyridinyl)-2-pyrimi-                                                      26.8                                                dinamine                                                                       4-[[4-(4-(Pyridinyl)-2-pyrimidinyl]amino]-                                                                3.3                                                 phenol                                                                           .sub.--N--[4-[2-(Dimethylamino)ethoxy]phenyl]-4-(4-                                                     1.5                                                 pyridinyl)-2-pyrimidinamine                                                     .sub.--N--[4-[2-(Dimethylamino)ethoxy]phenyl] .sub.--N', .sub.--N'--                                     9.1                                                 dimethyl- .sub.--N--[4-(4-pyridinyl)-2-pyrimidiny]-                            1,2-ethanediamine                                                               .sub.--N--[4-[3-Dimethylamino)propoxy]phenyl]-4-(4-                                                      1.3                                                 pyridinyl)-2-pyrimidinamine                                                     .sub.--N--[4-[2-(Diethylamino)ethoxy]phenyl]-4-(4-                                                       0.2                                                 pyridinyl)-2-pyrimidinamine                                                    4-[2-[(4-Methoxyphenyl)amino]-4-pyrimidinyl]-                                                             33.3                                                1-methylpyridinium, iodide                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimi-                                      1.0                                                 dinyl)]-1,3-benzenediamine, sulfate                                             .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-thienyl)-2-pyrimidinyl]-                                  2.4                                                 1,3-benzenediamine                                                              .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(5-methyl-2-furanyl)-2-                                      1.6                                                 pyrimidinyl]-1,3-benzenediamine                                                 .sub.--N'--[4-(2,5-Dimethyl-3-furanyl)-2-pyrimidinyl]-                                                   <24                                                  .sub.--N, .sub.--N--dimethyl-1,3-benzenediamine                                .sub.--N--[2-(Diethylamino)ethyl]-4-[[4-(3-pyridin-                                                      0.8                                                 yl)-2-pyrimidinyl]amino]benzamide                                              4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]-                                                                 5.8                                                 phenoxy]acetic acid, ethyl ester                                                .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimidin-                                    1.1                                                 yl]-1,4-benzenediamine                                                          .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-methyl-6-(2-pyridinyl)-2-                                    31.8                                                pyrimidinyl]-1,4-benzenediamine                                                 .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)phenyl]-4-(4-pyridin-                                            12.3                                                yl)-2-pyrimidinamine                                                            .sub.--N--[4-(4-Pyridinyl)-2-pyrimidinyl]-1,4-benzene-                                                   3.0                                                 diamine, hydrochloride                                                          .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(3-pyridinyl)-2-pyrimi-                                       1.7                                                 dinyl]-1,4-benzenediamine                                                       .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)phenyl]-4-(3-pyridin-                                            1.3                                                 yl)-2-pyrimidinamine                                                           1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                              11.4                                                phenyl]ethanone, oxime                                                         1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                              5.1                                                 phenyl]ethanone, O--methyloxime                                                 .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidin-                                    10.1                                                yl]-1,4-benzenediamine                                                          .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)phenyl]-4-(2-pyridin-                                            1.8                                                 yl)-2-pyrimidinamine                                                           4-(2-Furanyl)- .sub.--N--[4-(1 .sub.--H--imidazol-1-yl)phenyl]-                                           2.2                                                 2-pyrimidinamine                                                                .sub.-- N--Methyl-4-[[4-(3-pyridinyl)-2-pyrimidinyl]-                                                    4.6                                                 amino]-benzamide                                                                .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(5-methyl-2-thienyl)-2-                                      5.7                                                 pyrimidinyl]-1,3-benzenediamine                                                 .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-thienyl)-2-pyrimidinyl]-                                  2.1                                                 1,4-benzenediamine                                                              .sub.--N--[1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                        0.4                                                 amino]phenyl]ethyl]formamide                                                    .sub.--N--[4-[1-Aminoethyl)phenyl]-4-(3-pyridinyl)-                                                      0.8                                                 2-pyrimidinamine, trihydrochloride                                             4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]benz-                                                             0.2                                                 enesulfonamide                                                                  .sub.--N--(3-Chlorophenyl)-4-(4-pyridinyl)-2-pyrimi-                                                     3.1                                                 dinamine                                                                        .sub.--N--(3-Chlorophenyl)-4-(3-pyridinyl)-2-pyrimi-                                                     1.5                                                 dinamine                                                                        .sub.--N--(3-Methoxyphenyl)-4-(3-thienyl)-2-pyrimidin-                                                   1.7                                                 amine                                                                           .sub.--N--Methyl- .sub.--N--[4-[[4-(3-pyridinyl)-2-pyrimidin-                                            1.1                                                 yl]amino]phenyl]acetamide                                                       .sub.--N--Methyl- .sub.--N--[4-[[4-(4-pyridinyl)-2-pyrimidin-                                            0.1                                                 yl]amino]phenyl]acetamide                                                       .sub.--N--Methyl- .sub.--N--[4-[[4-(2-pyridinyl)-2-pyrimidin-                                            0.6                                                 yl]amino]phenyl]acetamide                                                      [4-(2-Furanyl)- .sub.--N--(3-methoxyphenyl)-2-pyrimi-                                                     0.3                                                 dinamine                                                                       4-(2-Benzofuranyl)- .sub.--N--(3-methoxyphenyl)-2-                                                        1.2                                                 pyrimidinamine                                                                 Oxo[phenyl[4-(4-pyridinyl)-2-pyrimidinyl]-                                                                2.1                                                 amino]acetic acid, ethyl ester                                                  .sub.--N--[4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]-                                                     5.3                                                 phenyl]acetamide                                                                .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-furanyl)-5-methyl-2-                                      40                                                  pyrimidinyl]-1,3-benzenediamine                                                 .sub.--N--[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                     3.6                                                 phenyl]acetamide                                                               4-[[4-(2-Pyridinyl)-2-pyrimidinyl]amino]-                                                                 4.5                                                 benzenesulfonamide                                                              .sub.--N--[4-[[4-(2-Pyridinyl)-2-pyrimidinyl]amino]-                                                     1.5                                                 phenyl]acetamide                                                                .sub.--N--(3-Methoxyphenyl)-4-(2-thienyl)-2-pyrimi-                                                      0.9                                                 dinamine                                                                        .sub.--N--[4-(4-Methyl-1-piperazinyl)phenyl]-4-(3-                                                       1.5                                                 pyridinyl)-2-pyrimidinamine                                                     .sub.--N--(3-Methoxyphenyl)-4-(5-methyl-2-thienyl)-                                                      2.3                                                 2-pyrimidinamine                                                                .sub.--N--(3-Chlorophenyl)-4-(2-pyridinyl)-2-pyrimi-                                                     1.3                                                 dinamine                                                                       4-(2-Furanyl)- .sub.--N--[4-(4-methyl-1-piperazinyl)-                                                     1.8                                                 phenyl]-2-pyrimidinamine                                                        .sub.--N--[4-(4-Methyl-1-piperazinyl)phenyl]-4-(4-                                                       0.6                                                 pyridinyl)-2-pyrimidinamine                                                     .sub.--N--(3-Methoxyphenyl)-4-(2,5-dimethyl-3-furan-                                                     5.8                                                 yl)-2-pyrimidinamine                                                            .sub.--N--[4-(2-Pyridinyl)-2-pyrimidinyl]-1,4-benzene-                                                   1.0                                                 diamine, dihydrochloride                                                        .sub.--N--(3-Fluorophenyl)-4-(4-pyridinyl)-2-pyrimi-                                                     0.7                                                 dinamine                                                                        .sub.--N--(3-Fluorophenyl)-4-(3-pyridinyl)-2-pyrimi-                                                     3.3                                                 dinamine                                                                        .sub.--N--(3-Fluorophenyl)-4-(2-pyridinyl)-2-pyrimi-                                                     0.9                                                 dinamine                                                                       1-[3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                              4.1                                                 phenyl]ethanone                                                                 .sub.--N--Methyl- .sub.--N'--[4-(3-pyridinyl)-2-pyrimidinyl]-                                            2.1                                                 1,4-benzenediamine                                                              .sub.--N--[4-(1-Methylethyl)phenyl]-4-(3-pyridinyl)-                                                     1.1                                                 2-pyrimidinamine                                                                .sub.--N--Methyl- .sub.--N'--[4-(2-pyridinyl)-2-pyrimidinyl]-                                            1.4                                                 1,4-benzenediamine                                                              .sub.--N--(3-Ethylphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                      1.7                                                 dinamine                                                                        .sub.--N--(3-Ethylphenyl)-4-(2-pyridinyl)-2-pyrimi-                                                      1.4                                                 dinamine                                                                       3-[[4-(2-Pyridinyl)-2-pyrimidinyl]amino]ben-                                                              0.7                                                 zenesulfonamide                                                                3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]ben-                                                              0.2                                                 zenesulfonamide                                                                 .sub.--N--[4-(1,1-Dimethylethyl)phenyl]-4-(2-thienyl)-                                                   4.6                                                 2-pyrimidinamine                                                                .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(2-furanyl)-2-pyrimidinyl]-                                   3.4                                                 1,4-benzenediamine                                                             3-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]-                                                                 0.5                                                 benzenesulfonamide                                                              .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-pyridinyl)-2-pyrimi-                                      36.2                                                dinyl]-1,2-benzenediamine, fumarate                                            2-[1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]                                                            8.1                                                 phenyl]ethylidene]hydrazinecarboxamide                                          .sub.--N--[4-[2-[bis(1,1-Dimethylethyl)amino]ethoxy]-                                                    4.6                                                 phenyl]-4-(3-pyridinyl)-2-pyrimidinamine -α-Methyl-4-[[4-(3-pyridiny     l)-2-pyrimidinyl]-         4.5                                                 amino]benzenemethanol                                                           .sub.--N--[1-[3-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                        4.6                                                 amino]phenyl]ethyl]formamide                                                     .sub.--N--[3-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]-                                                    2.1                                                 phenyl]acetamide                                                                .sub.--N--[3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                     5.0                                                 phenyl]acetamide                                                                .sub.--N--[4-(3-Pyridinyl)-2-pyrimidinyl]-1,3-benzene-                                                   0.4                                                 diamine, dihydrochloride                                                        .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(5-methyl-2-furanyl)-2-                                       28.0                                                pyrimidinyl]1,4-benzenediamine                                                  .sub.--N--(3-Methoxyphenyl)-4-(5-methyl-2-furanyl)-2-                                                    1.2                                                 pyrimidinamine                                                                  .sub.--N--[3-[[4-(2-Pyridinyl)-2-pyrimidinyl]amino]-                                                     0.3                                                 phenyl]acetamide                                                                .sub.--N--[3-(1 .sub.--H--Imidazol-1-yl)phenyl]-4-(2-pyri-                                               0.1                                                 dinyl)-2-pyrimidinamine                                                         .sub.--N--[4-(4-Pyridinyl)-2-pyrimidinyl]-1,3-benzene-                                                   1.0                                                 diamine                                                                         .sub.--N--[2-Methyl-4-[[4-(4-pyridinyl)-2-pyrimi-                                                        1.2                                                 dinyl]amino]phenyl]acetamide                                                   2-Methyl- .sub.--N--[4-(4-pyridinyl)-2-pyrimidinyl]-                                                      0.9                                                 1,4-benzenediamine, dihydrochloride                                             .sub.--N--[4-(2-Pyridinyl)-2-pyrimidinyl]-1,3-benzene-                                                   0.2                                                 diamine                                                                         .sub.--N--[4-[[4-(5-Methyl-2-thienyl)-2-pyrimidinyl]-                                                    0.3                                                 amino]phenyl]acetamide                                                          .sub.--N--[3-(1-Aminoethyl)phenyl]-4-(3-pyridinyl)-2-                                                    5.1                                                 pyrimidinamine, trihydrochloride                                                .sub.--N--[3-[2-(Diethylamino)ethoxy]phenyl]-4-(3-                                                       2.8                                                 pyridinyl)-2-pyrimidinamine                                                     .sub.--N--(2-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimi-                                                    9.8                                                 dinamine                                                                        .sub.--N--[4-[[4-(2-Thienyl)-2-pyrimidinyl]amino]-                                                       0.2                                                 phenyl]acetamide                                                                .sub.--N--[2-Methyl-4-[4-(3-pyridinyl)-2-pyrimidinyl]-                                                   1.8                                                 phenyl]acetamide                                                                .sub.--N'--[4-(2-Benzofuranyl)-2-pyrimidinyl]- .sub.--N, .sub.--N--                                      6.2                                                 diethyl-1,4-benzenediamine                                                      .sub.--N--[4-[[4-(2-Furanyl)-2-pyrimidinyl]amino]-                                                       0.7                                                 phenyl]acetamide                                                                .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)-3-(trifluoromethyl)-                                            0.4                                                 phenyl]-4-(4-pyridinyl)-2-pyrimidinamine                                        .sub.--N--[3-(1 .sub.--H--Imidazol-1-yl)phenyl]-4-(3-pyri-                                               0.1                                                 dinyl)-2-pyrimidinamine                                                        2-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                                 23.5                                                phenol                                                                         4-(2-Furanyl)- .sub.--N--[3-(1 .sub.--H--imidazol-1-yl)phenyl]-                                           0.8                                                 2-pyrimidinamine                                                                .sub.--N--[3-[2-(Diethylamino)ethoxy]phenyl]-4-(2-                                                       1.3                                                 furanyl)-2-pyrimidinamine                                                       .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)-3-(trifluoromethyl)-                                            1.6                                                 phenyl]-4-(2-pyridinyl)-2-pyrimidinamine                                        .sub.--N--[3-[2-(Diethylamino)ethoxy]phenyl]-4-(2-                                                       0.6                                                 thienyl)-2-pyrimidinamine                                                       .sub.--N--[3-[2-(Diethylamino)ethoxy]phenyl]-4-(4-                                                       0.7                                                 pyridinyl)-2-pyrimidinamine                                                     .sub.--N--[4-(4-Pyridinyl)-2-pyrimidinyl]-1,4-ben-                                                       2.4                                                 zenediamine                                                                    N--[3-(1H--Imidazol-1-yl)phenyl]-4-(4-pyridinyl)-                                                         0.4                                                 2-pyrimidinamine                                                               N--[3-(1H--Imidazol-1-yl)phenyl]-4-(2-thienyl)-2-                                                         0.2                                                 pyrimidinamine                                                                 ______________________________________                                    

The ability of these compounds to inhibit lipoxygenase activity in terms of the suppression of the release and biosynthesis of leukotriene B4(LTB4) and 5-hydroxy-eicosatetraenoic acid (5-HETE) was measured as follows.

In this assay 3×10⁷ peritoneal neutrophils derived from guinea pigs were incubated at 37° C. in Dulbeccos buffer containing 50 mM tris buffer (pH 7.4). Five minutes before the addition of 100 μM arachidonic acid and 20 μM calcium ionophore (A23187), control vehicle or the test compounds were added to the neutrophils at a concentration of 10 μg/ml.

Three minutes after the addition of arachidonic acid and calcium ionophore the total lipid was partitioned into chloroform after adjusting the pH to 3 with citric acid and the addition of equal parts of methanol and chloroform.

The 5-HETE and LTB4 were resolved by HPLC using a 5 μM 4×25 cm octadecyl silica column (IBM Instruments) with 70-80% methanol in water adjusted to pH 3.0 with acetic acid. As the mobile phase was pumped at 1.0 ml/minute, LTB4 and 5-HETE were detected by absorbance at 270 and 236 nm, respectively.

LTB4 and 5-HETE were quantitated by comparison with the control and the results were expressed as a percent of control. The lower the percentage, the more active the compound.

The results of this test on representative compounds of this invention appear in Table II.

                  TABLE II                                                         ______________________________________                                         Inhibition of Neutrophil Lipoxygenase from                                     Immunologically Stimulated Guinea Pig Neutrophiles                                                   % Inhibition                                             Compound                LTB4    5-HETE                                         ______________________________________                                         4-(3-Pyridinyl)- --N--[3-trifluoromethyl)-                                                             58.1                                                   phenyl]-2-pyrimidinamine                                                        --N--(4-Acetylphenyl)-4-(3-pyridinyl)-2-                                                                      37.0                                           pyrimidinamine                                                                  --N--(4-Fluorophenyl)-4-(2-pyridinyl)-2-                                                                      45.0                                           pyrimidinamine                                                                  --N--(4-Methylphenyl)-4-(4-pyridinyl)-2-                                                                      45.0                                           pyrimidinamine                                                                  --N--(4-Fluorophenyl)-4-(4-pyridinyl)-2-                                                                      53.0                                           pyrimidinamine                                                                 4-(3-Pyridinyl)- --N--[3-trifluoromethyl)-                                                                     58.0                                           phenyl]-2-pyrimidinamine                                                        --N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine                                                                  58.0                                            --N--(3-Methylphenyl)-4-(3-pyridinyl)-2-                                                                      40.0                                           pyrimidinamine                                                                  --N--[4-Ethylphenyl)-4-(4-pyridinyl)-2-                                                               33.9    41.0                                           pyrimidinamine                                                                  --N--(4-Ethylphenyl)-4-(2-pyridinyl)-2-                                                               29.5    41.0                                           pyrimidinamine                                                                 4-(2-Furanyl)- --N--(3-methylphenyl)-2-pyrimi-                                                          7.4     3.0                                           dinamine                                                                        --N--[4-(4-Methyl-1-piperazinyl)phenyl]-4-                                                            48.0                                                   (2-thienyl)-2-pyrimidinamine                                                    --N--(4-Ethylphenyl)-4-(6-methyl-3-pyridin-                                                           53.4    54.0                                           yl)-2-pyrimidinamine                                                            --N--(3-Methylphenyl)-4-pyrazinyl-2-pyrimi-                                                                   50.0                                           dinamine                                                                        --N--(3-Ethylphenyl)-4-(4-pyridinyl)-2-                                                               36.4    28.7                                           pyrimidinamine                                                                  --N--(2,3-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                          58.4                                                   pyrimidinamine                                                                  --N--Phenyl-4-(3-thienyl)-2-pyrimidinamine                                                                    56.0                                            --N--(3-Methylphenyl)-4-(3-thienyl)-2-pyrimi-                                                                 48.0                                           dinamine                                                                         --N--(4-Ethylphenyl)-4-(3-thienyl)-2-pyrimi-                                                                 56.0                                           dinamine                                                                        --N--(2,4-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                                  54.0                                           pyrimidinamine                                                                  --N--(3,5-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                          53.1    54.0                                           pyrimidinamine                                                                  --N--(2-Methoxyphenyl)-4-(4-pyridinyl)-2-                                                             17.4    21.0                                           pyrimidinamine                                                                  --N--(2,5-Dimethoxyphenyl)-4-(4-pyridinyl)-                                                           43.2    47.0                                           2-pyrimidinamine                                                                --N--(2,4-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                          37.0    43.0                                           pyrimidinamine                                                                  --N--(2-Methoxy-5-methylphenyl)-4-(2-pyridin-                                                                 54.0                                           yl)-2-pyrimidinamine                                                           4-(4-Pyridinyl)- --N--(2,4,6-trimethylphenyl)-                                                         53.6                                                   2-pyrimidinamine                                                               4-(2-Furanyl)- --N--(4-methoxyphenyl)-2-                                                                       44.0                                           pyrimidinamine                                                                 4-(2-Furanyl)- --N--[3-trifluoromethyl)-                                                               45.0    49.0                                           phenyl]-2-pyrimidinamine                                                        --N--(4-Fluorophenyl)-4-(2-furanyl)-2-pyrimi-                                                         33.0                                                   dinamine                                                                        --N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                         58.0                                                   compound with 2-hydroxy-1,2,3-propanetri-                                      carboxylate (2:1)                                                               --N--[(3,4-Dimethylphenyl)methyl]-4-(4-                                                               24.0    36.0                                           pyridinyl)-2-pyrimidinamine                                                     --N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                         56.0                                                   sulfate                                                                        4-(2-Benzofuranyl)- --N--(3-methylphenyl)-2-                                                           46.1                                                   pyrimidinamine                                                                  --N--(4-Ethylphenyl)-4-(4-pyridinyl)-2-                                                                       19.0                                           pyrimidinamine                                                                  --N--(3,4-Dimethylphenyl)-4-(4-pyridinyl)-2-                                                                  19.0                                           pyrimidinamine                                                                  --N--(3,4-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                          17.3    35.0                                           pyrimidinamine                                                                  --N--(4-Fluorophenyl)-4-(3-thienyl)-2-pyrimi-                                                         51.6                                                   dinamine                                                                       4-(10 --H--Phenolthiazin-2-yl)- --N--phenyl-2-                                                                 48.0                                           pyrimidinamine                                                                 4-(1 --H--Indol-3-yl)- --N--phenyl-2-pyrimidin-                                                        41.2    39.0                                           amine                                                                           --N--(2-Methoxy-5-methylphenyl)-4-(4-pyridin-                                                         44.7    37.0                                           yl)-2-pyrimidinamine                                                            --N--(3-Methylphenyl)-4-(1-methyl-1 --H--pyrrol-                                                              60.0                                           2-yl)-2-pyrimidinamine                                                         4-(1-Methyl-1 --H--pyrrol-2-yl)- --N--phenyl-2-                                                                57.0                                           pyrimidinamine                                                                  --N--(4-Ethylphenyl)-4-(1 --H--indol-3-yl)-2-                                                         56.5                                                   pyrimidinamine                                                                  --N--[1,1'-Biphenyl]-4-yl-(4-pyridinyl)-2-                                                            37.1    45.0                                           pyrimidinamine                                                                 4-[[4-(4-Pyridinyl)-2-pyrimidinyl]-amino]-                                                             45.2    47.0                                           benzoic acid, methyl ester                                                      --N--(3-Methylphenyl)-4-(4-quinolinyl)-2-                                                             16.0                                                   pyrimidinamine                                                                  --N--Phenyl-4-(4-quinolinyl)-2-pyrimidinamine                                                         46.4    57.0                                            --N--(4-Ethylphenyl)-4-(4-quinolinyl)-2-                                                                      58.0                                           pyrimidinamine                                                                  --N--(3,5-Dimethylphenyl)-4-(2-furanyl)-2-                                                            56.1                                                   pyrimidinamine                                                                  --N--[4-(1,1-Dimethylethyl)phenyl]-4-(4-                                                              47.8    54.0                                           pyridinyl)-2-pyrimidinamine                                                     --N--Methyl- --N--phenyl-4-(2-pyridinyl)-2-                                                           58.1    54.0                                           pyrimidinamine                                                                  --N--Phenyl-4-(1 --H--pyrrol-2-yl)-2-pyrimidin-                                                       55.4                                                   amine                                                                           --N--(4-Ethylphenyl)-4-(1 --H--pyrrol-2-yl)-2-                                                        32.6    54.0                                           pyrimidinamine                                                                 4-(3-Pyridinyl)- --N--[3-(trifluoromethyl)-                                                            37.3    49.0                                           phenyl]-2-pyrimidinamine sulfate                                                --N--Phenyl-4-(4-pyridinyl)-2-pyrimidinamine,                                                         48.0    43.0                                           dihydrochloride                                                                4-(3-Methyl-2-thienyl)- --N--phenyl-2-pyrimi-                                                                  59.0                                           dinamine                                                                       4-(5-Methyl-2-furanyl)- --N--(3-methylphenyl)-                                                         59.6                                                   2-pyrimidinamine                                                               4-Methyl-6-(5-methyl-2-thienyl)- --N--phenyl-                                                          42.3    52.0                                           2-pyrimidinamine                                                                --N--[4-(Dimethylamino)phenyl]-4-(4-pyridin-                                                          16.6    12.4                                           yl)-2-pyrimidinamine                                                            --N--(3-Methoxyphenyl)-4-(4-pyridinyl)-2-                                                             31.2    50.0                                           pyrimidinamine                                                                  --N--[4-(Dimethylamino)phenyl]-4-(2-pyridin-                                                          20.1    17.2                                           yl)-2-pyrimidinamine                                                            --N--(3,5-Dimethylphenyl)-4-(3-pyridinyl)-                                                            50.7    56.0                                           2-pyrimidinamine                                                               4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                              35.8    47.0                                           benzoic acid, ethyl ester                                                       --N, --N--Dimethyl- --N--'[4-(3-pyridinyl)-2-pyrimi-                                                  43.4    34.0                                           dinyl]-1,4-benzenediamine                                                      4-(2,5-Dimethyl-3-furanyl)- --N--phenyl-2-                                                             46.9    56.0                                           pyrimidinamine                                                                  --N, --N--Dimethyl- --N'--[4-(4-pyridinyl)-2-                                                         40.7    37.0                                           pyrimidinyl]-1,4-benzenediamine, trihydro-                                     chloride                                                                        --N, --N--Dimethyl- --N'--[4-(2-pyridinyl)-2-pyrimi-                                                  37.6    39.0                                           dinyl]-1,4-benzenediamine, dihydrochloride                                     4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                                      30.0                                           phenol                                                                         3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]-                                                              36.1    50.0                                           benzoic acid, ethyl ester                                                       --N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                          50.0                                                   pyrimidinamine, sulfate                                                         --N--[4-(2-Propenyloxy)phenyl]-4-(3-pyridin-                                                          34.1                                                   yl)-2-pyrimidinamine                                                            --N'[4-(2-Furanyl)-2-pyrimidinyl]- --N, --N--dim-                                                     16.9    16.9                                           ethyl-1,4-benzenediamine                                                        --N, --N--Dimethyl- --N'--[4-(2-thienyl)-2-pyrimi-                                                    49.8    17.8                                           dinyl]-1,4-benzenediamine                                                       --N'--[4-(2,5-Dimethyl-3-furanyl)-2-pyrimi-                                                           21.6    17.0                                           dinyl]- --N, --N--dimethyl-1,4-benzenediamine                                   --N, --N--Dimethyl- --N'--[4-(3-methyl-2-thienyl)-                                                    16.4    13.6                                           2-pyrimidinyl]-1,4-benzenediamine                                               --N, --N--Dimethyl --N'--[4-(3-pyridinyl)-2-pyrimi-                                                   46.8    42.0                                           dinyl]-1,4-benzenediamine, trihydro-                                           chloride                                                                        --N, --N--Dimethyl- --N'--[4-(4-pyridinyl)-2-pyrimi-                                                  51.1                                                   dinyl]-1,3-benzenediamine                                                       --N, --N--Dimethyl-N'--[4-methyl-6-(4-pyridin-                                                         1.6    10.0                                           yl)-2-pyrimidinyl]-1,4-benzenediamine                                           --N--(3,5-Dimethylphenyl)-4-methyl-6-(3-                                                              32.7    40.0                                           pyridinyl)-2-pyrimidinamine                                                     --N'--[4-(2-Furanyl)-5-methyl-2-pyrimidinyl]-                                                          3.6                                                    --N, --N--dimethyl-1,4-benzendiamine                                          4-(2-Furanyl)-5-methyl- --N--phenyl-2-pyrimi-                                                          52.4                                                   dinamine, sulfate                                                               --N'--[4-(2-Benzofuranyl)-2-pyrimidinyl]- --N, --N--                                                  22.9    30.0                                           dimethyl-1,4-benzenediamine                                                    4-Methyl- --N--phenyl-6-(2-pyridinyl)-2-                                                               30.3    42.0                                           pyrimidinamine                                                                 4-[[4-(4-Pyridinyl)-2-pyrimidinyl]-amino]-                                                                     36.0                                           phenol                                                                          --N--(4-Methoxyphenyl)- --N--methyl-4-(4-                                                             57.4                                                   pyridinyl-2-pyrimidinamine                                                      --N, --N--Dimethyl- --N'--[4-(2-thienyl)-2-pyrimi-                                                    39.6    50.0                                           dinyl]-1,3-benzenediamine                                                       --N, --N--Dimethyl- --N'--[4-(5-methyl-2-furanyl)-2-                                                  31.1    37.7                                           pyrimidinyl]-1,3-benzenediamine                                                 --N--Methyl- --N'--[4-(2-pyridinyl)-2-pyrimi-                                                         24.1    53.6                                           dinyl]-1,4-benzenediamine                                                       --N--[1-[3-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                          34.0                                                   amino]phenyl]ethyl]formamide                                                    --N--[4-[[4-(5-Methyl-2-thienyl)-2-pyrimi-                                                            51.0    46.0                                           dinyl]amino]phenyl]acetamide                                                    --N'--[4-(2-Benzofuranyl)-2-pyrimidinyl]- --N, --N--                                                  51.0    45.0                                           diethyl-1,4-benzenediamine                                                      --N--[4-(1 --H--Imidazol-1-yl)-3-(trifluoro-                                                          20.0    16.0                                           methyl)phenyl]-4-(4-pyridinyl)-2-                                              pyrimidinamine                                                                  --N--[4-(5-Methyl-2-thienyl)-2-pyrimidinyl]-                                                          47.0    28.0                                           1,4-benzenediamine, dihydrochloride                                             --N--[3-(1 --H--Imidazol-1-yl)phenyl]-4-(3-pyri-                                                      50.0    51.0                                           dinyl)-2-pyrimidinamine                                                         --N--[3-(1 --H--Imidazolyl)phenyl]-4-(2-thienyl)-                                                     50.0    39.0                                           2-pyrimidinamine                                                                --N--[4-(2-Furanyl)-2-pyrimidinyl]-1,4-ben-                                                                   54.0                                           zenediamine, dihydrochloride                                                    --N--[4-(1 --H--Imidazol-1-yl)-3-(trifluoro-                                                                  19.0                                           methyl)phenyl]-4-(2-pyridinyl)-2-pyrimi-                                       dinamine                                                                       4-[ [4-(2-Furanyl)-2-pyrimidinyl]amino]-                                                               47.0                                                   benzenesulfonamide                                                             ______________________________________                                    

The novel compounds of the present invention are effective as antiasthmatic agents in mammals when administered in amounts ranging from about 0.1 mg to about 100 mg/kg of body weight per day. A preferred dosage regimen for optimum results would be from about 0.1 mg to about 25 mg/kg of body weight per day, and such dosage units are employed that a total of from about 7 mg to about 1.8 g of the active compound for a subject of about 70 kg of body weight are administered in a 24 hour period. This dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decided practical advantage is that these active compounds may be adminstered in any convenient manner such as by the oral, aerosol, intravenous, intramuscular, or subcutaneous routes.

The active compounds may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets or they may be incorporated directly with the food of the diet. For oral therapeutic administration, these active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound is such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 5 and 200 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, these active compounds may be incorporated into sustained-release preparations and formulations.

Compositions according to the present invention having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.10% to 10.0% by weight of active compound in a vehicle consisting of a polyhydric aliphatic alcohol or mixtures thereof. Especially satisfactory are glycerin, propylene glycol, and polyethylene glycols. The polyethylene glycols consist of a mixture of non-volatile, normally liquid, polyethylene glycols which are soluble in both water and organic liquids and which have molecular weights of from about 200 to 1500. Although various mixtures of the aforementioned non-volatile polyethylene glycols may be employed, it is preferred to use a mixture having an average molecular weight of from about 200 to about 400.

In addition to the active compound, the parenteral solutions may also contain various preservatives which may be used to prevent bacterial and fungal contamination. The preservatives which may be used for these purposes are, for example, myristyl-gamma-picolinium chloride, benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-alpha-glycerol ether, methyl and propyl parabens, and thimerosal. As a practical matter, it is also convenient to employ antioxidants. Suitable antioxidants include, for example, sodium bisulfite, sodium metabisulfite, and sodium formaldehyde sulfoxylate. Generally, from about 0.05% to about 0.2% concentrations of anti-oxidant are employed.

These compounds may also be administered by inhalation using conventional Aerosol® formulations.

The invention will be described in greater detail in conjunction with the following specific examples.

EXAMPLE 1 4-(3-Pyridinyl)-N-[3-(trifluoromethyl)phenyl]-2-pyrimidinamine

A 7.04 g amount of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one (U.S. Pat. No. 4,281,000) and 18.72 g of [3-(trifluoromethyl)phenyl]guanidine carbonate in 500 ml of n-propanol was heated at reflux temperature for 16 hours. The solvent was evaporated to near dryness, then water was added and the precipitate which formed was collected by filtration, then recrystallized from hexane to give 5.55 g of the desired product, mp 170°-171° C.

EXAMPLE 2 N-(4-Methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinamine

A mixture of 14.4 g of 3-dimethylamino-1-(3-pyridinyl)-2-propen-1-one and 16.1 g of 4-methoxyphenyl guanidine carbonate in 200 ml of isopropanol was heated at reflux for 20 hours. The reaction mixture was cooled, the crude product was collected by filtration and washed with water. The material was recrystallized from isopropanol to give the desired product as light yellow crystals, mp 121°-122° C.

EXAMPLE 3 N-(4-Methoxyphenyl)-4-(4-pyridinyl)-2-pyrimidinamine

A 14.4 g amount of 3-dimethylamino-1-(4-pyridinyl)-2-propen-2-one (U.S. Pat. No. 4,281,000) and 16.1 g of 4-methoxyphenylguanidine carbonate in 200 ml of isopropanol was heated at reflux for 24 hours. The solvent was evaporated to 1/3 volume, then the mixture was cooled in an ice-bath to crystallize the product. The product was collected by filtration and washed with water, then with isopropanol. The material was recrystallized from isopropanol/ethylene glycol monomethyl ether to give 16.7 g of the desired product as yellow crystals, mp 174°-175° C.

EXAMPLE 4 N-(4-Methoxyphenyl)-4-(2-thienyl)-2-pyrimidinamine

A mixture of 10.9 g of 3-dimethylamino-1-(2-thienyl)-2-propen-1-one (U.S. Pat. No. 4,374,988) and 11.8 g of 4-methoxyphenylguanidine carbonate in 150 ml of isopropanol was heated at reflux for 48 hours. The solution was cooled, then filtered, giving 9.0 g of the desired product as yellow crystals, mp 158°-160° C.

EXAMPLE 5 4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]benzoic acid, methyl ester

A solution of 10.0 g of 4-guanidinobenzoic acid, hydrochloride in 310 ml of methanol was mixed with 6.0 ml (9.68 g) of thionyl chloride at 0° C. for 15 minutes, then stirred for one hour at room temperature and then heated at reflux for 16 hours. The solvent ws removed in vacuo and the solid was washed with ether and air dried to give 11.4 g of white crystals (A).

The above procedure was repeated using 20.0 g of 4-guanidinobenzoic acid, 11.9 ml (19.4 g) of thionyl chloride and 600 ml of methanol to give 22.6 g of white crystals (B).

The products (A) and (B) were combined and recrystallized from absolute ethanol. The product was washed with cold absolute ethanol and air dried giving 26.2 g of p-guanidinobenzoic acid, methyl ester, hydrochloride as white crystals, mp 137°-138.5° C. (dec.).

A 9.15 g amount of the above compound was partially dissolved in 100 ml of methanol (stored over 4A molecular sieves) and 2.15 g of sodium methoxide was added. The mixture was stirred briefly, then 7.0 g of 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one was added and the mixture was heated under argon with stirring for 21.5 hours. The reaction mixture was cooled in an ice bath, then filtered and washed with cold methanol. The residue was dissolved in a mixture of dichloromethane and methanol and filtered to remove sodium chloride. The filtrate was concentrated on a steam bath until crystal formation. The mixture was allowed to stand at room temperature for 16 hours then was filtered. The precipitate was washed with ice cold methanol then dried and gave 5.8 g of the desired product, mp 194.5°-196.5° C.

EXAMPLE 6 3-Dimethylamino-1-(3-indolyl)-2-propen-1-one

A mixture of 3.18 g of 3-acetylindole and 5.17 ml. (4.36 g) of tert-butoxybis(dimethylamino)methane was heated on a steam bath for 4 hours. The cooled reaction mixture was triturated with n-hexanes and gave a semi-solid. The solvent was removed in vacuo and the material was triturated with dichloromethane giving 3.08 g of the desired compound as a tan crystalline solid, mp 239°-245° C.

EXAMPLE 7 3-Dimethylamino-1-(5-methyl-2-thienyl)-2-propen-1-one

A mixture of 56.08 g of 2-acetyl-5-methylthiophene and 250 ml of N,N-dimethylformamide dimethylacetal was heated on a steam bath under an air condenser for 16 hours. The mixture was cooled in an ice bath and filtered giving 66.82 g of the desired compound, mp 118°-121° C.

EXAMPLE 8 3-(Dimethylamino)-1-(5-methyl-2-furanyl)-2-propen-1-one

A mixture of 37.24 g of 2-acetyl-5-methylfuran and 150 ml of N,N-dimethylformamide dimethylacetal was heated on a steam bath under an air condenser for 16.5 hours. The solvent was removed in vacuo and the residue taken up in dichloromethane and passed through a short column of magnesium silicate. The filtrate was evaporated on a steam bath with the addition of n-hexanes to a volume of 100-150 ml. Cooling with scratching gave 28.31 g of the desired compound, mp 123°-125° C.

EXAMPLE 9 3-(Dimethylamino)-1-(1H-pyrrol-2-yl)-(E)-2-propen-1-one

A mixture of 39.6 g of 2-acetylpyrrole and 104 ml (87.7 g) of tert-butoxy bis(dimethylamino)methane was heated on a steam bath for 20 minutes. The reaction was allowed to subside, then heating was continued for 6 hours. The mixture solidified then was slurried in hexane with chilling. The crude product was collected, washed with hexane and dried. The solid was dissolved in chloroform containing 5% methanol and filtered through magnesium silicate. The eluent was evaporated in vacuo and the residue was recrystallized from dichloromethane/hexane containing a small amount of methanol. The solid was collected, washed with hexane then dried in vacuo giving 25.1 g of the desired compound as yellow crystals, mp 192°-193° C. (dec.).

The following 3-(dimethylamino)acrylophenone intermediate compounds listed in Table III were prepared in a similar manner to the procedures described in Examples 6-8 and by those described in U.S. Pat. Nos. 4,281,000, 4,374,988 and in Ser. No. 672,753, filed on Nov. 19, 1984.

                  TABLE III                                                        ______________________________________                                         3-(Dimethylamino)acrylophenone Intermediates                                    ##STR5##                                                                       ##STR6##                                                                      Ex.   R.sub.3          R.sub.4 R.sub.5                                                                             MP °C.                              ______________________________________                                         10    2-Furanyl        H       H    84-86                                      11    2-pyridinyl      H       H    127-130                                    12    2-furanyl        CH.sub.3                                                                               H    Oil                                        13    4-pyridinyl      CH.sub.3                                                                               H    106-108                                    14    4-methyl-3-pyridinyl                                                                            H       H    116-118                                    15    4-methyl-3-pyridinyl                                                                            H       CH.sub.3                                                                            119-120                                    16    2-pyrazinyl      H       H    132-133                                    17    3-thienyl        H       H    89-90                                      18    4-quinolinyl     H       H                                               19    3-methyl-2-thienyl                                                                              H       H    45-49                                      20    1-methyl-1 --Hpyrrol-2-yl                                                                       H       H    94-95                                      21    5-methyl-2-thienyl                                                                              H       CH.sub.3                                                                            123-126                                    22    2,5-dimethyl-3-furanyl                                                                          H       H    91-95                                      23    2-pyridinyl      H       CH.sub.3                                                                            68-70                                      24    2-thienyl        H       CH.sub.3                                                                            97-99                                      25    4-pyridinyl      H       CH.sub.3                                                                            88-89                                      26    3-pyridinyl      H       CH.sub.3                                                                            62-64                                      27    3-pyridinyl      CH.sub.3                                                                               H    76-78                                      28    3-methyl-2-pyridinyl                                                                            H       H    97-98                                      29    2-benzofuranyl   H       H    137.0-138.5                                30    3-pyridinyl      H       H    97-99                                      31    2-phenothiazine  H       H                                               ______________________________________                                    

EXAMPLES 32-251 4,5,6-Substituted-2-pyrimidinamines

The following 4,5,6-substituted-2-pyridinamine final products listed in Table IV were obtained by reacting a 3-(dimethylamino)acrylophenone from Table III and an appropriately substituted phenylguanidine base, carbonate, sulfate, nitrate or hydrochloride salt in an inert solvent such as absolute ethanol, n-propanol, isopropanol, 2-methoxyethanol, or n-butanol and the like, with or without a base such as sodium hydroxide, potassium hydroxide or potassium carbonate and the like by heating at the reflux temperature for from 6-90 hours, then recovering the product in a conventional manner with recrystallization from solvents such as n-propanol, isopropanol, absolute ethanol and the like.

                                      TABLE IV                                     __________________________________________________________________________     2-Amino-4,5,6-substituted Pyrimidinamines                                         Acrylophenone                                                                          Phenylguanidine                                                     Ex.                                                                               Source  Precursor     Product            MP° C.                      __________________________________________________________________________      32                                                                               Ex. 12  Phenylguanidine carbonate                                                                    4-(2-Furanyl)-5-methyl- .sub.-- .sub.--N--phenyl-                              2-                 141-142                                                     pyrimidinamine                                         33                                                                               Ex. 3   [3-(Trifluoromethyl)-                                                                        4-(4-Pyridinyl)- .sub.-- .sub.--N--[3-(trifluoro-                                                 198-200                                       phenyl]guanidine carbonate                                                                   methyl)phenyl]-2-pyrimidinamine                        34                                                                               Ex. 1   Phenylguanidine carbonate                                                                     .sub.-- .sub.--N--Phenyl-4-(3-pyridinyl)-2-pyrim                              i-                 147-148                                                     dinamine                                               35                                                                               Ex. 1   (4-Acetylphenyl)guanidine                                                                     .sub.--N--(4-Acetylphenyl)-4-(3-pyridinyl)-                                                      181-183                                                     2-pyrimidinamine                                       36                                                                               Ex. 1   (4-Fluorophenyl)guanidine                                                                     .sub.--N--(4-Fluorophenyl)-4-(3-pyridinyl)-                                                      167-169                                       carbonate     2-pyrimidinamine                                       37                                                                               Ex. 11  (4-Methoxyphenyl)guani-                                                                       .sub.--N--(4-Methoxyphenyl)-4-(2-pyridinyl)-                                                     162-164                                       dine carbonate                                                                               2-pyrimidinamine                                       38                                                                               Ex. 3   (4-Fluorophenyl)guanidine                                                                     .sub.--N--(4-Fluorophenyl)-4-(4-pyridinyl)-                                                      168-188                                       carbonate     2-pyrimidinamine                                       39                                                                               Ex. 1   (4-Bromophenyl)guanidine                                                                      .sub.--N--(4-Bromophenyl)-4-(3-pyridinyl)-                                                       174-175                                       carbonate     2-pyrimidinamine                                       40                                                                               Ex. 4   (4-Fluorophenyl)guanidine                                                                     .sub.--N--(4-Fluorophenyl)-4-(2-thienyl)-2-                                                      176-178                                       carbonate     pyrimidinamine                                         41                                                                               Ex. 11  [3-(Trifluoromethyl)-                                                                        4-(2-Pyridinyl)- .sub.--N--[3-(trifluoro-                                                         161-162                                       phenyl]guanidine carbonate                                                                   methyl)phenyl]-2-pyrimidinamine                        42                                                                               Ex. 4   Phenylguanidine carbonate                                                                     .sub.--N--Phenyl-4-(2-thienyl)-2-pyrimidin-                                                      137-139                                                     amine                                                  43                                                                               Ex. 1   3-Chloro-4-methylphenyl-                                                                      .sub.--N--(3-Chloro-4-methylphenyl)-4-(3-                                                        140-145                                       guanidine carbonate                                                                          pyridinyl)-2-pyrimidinamine                            44                                                                               Ex. 11  3-Methylphenylguanidine                                                                       .sub.--N--(3-Methylphenyl)-4-(2-pyridinyl)-                                                      135-137                                       carbonate     2-pyrimidinamine                                       45                                                                               Ex. 3   3-Methylphenylguanidine                                                                       .sub.--N--(3-Methylphenyl)-4-(4-pyridinyl)-                                                      157-159                                       carbonate     2-pyrimidinamine                                       46                                                                               Ex. 3   Phenylguanidine carbonate                                                                     .sub.--N--Phenyl-4-(4-pyridinyl)-2-pyrimi-                                                       153-154                                                     dinamine                                               47                                                                               Ex. 1   3-Methylphenylguanidine                                                                       .sub.--N--(3-Methylphenyl)-4-(3-pyridinyl)-                                                      102-103                                       carbonate     2-pyrimidinamine                                       48                                                                               Ex. 3   4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-4-(4-pyridinyl)-                                                       138-140                                       carbonate     2-pyrimidinamine                                       49                                                                               Ex. 13  4-Ethylphenylguanidine                                                                        .sub.--N--(-4-Ethylphenyl)-5-methyl-4-(4-                                                        132-133                                       carbonate     pyridinyl)-2-pyrimidinamine                            50                                                                               Ex. 3   3,4-Dichlorophenylguani-                                                                      .sub.--N--(3,4-Dichlorophenyl)-4-(4-pyri-                                                        214-216                                       dine carbonate                                                                               dinyl)-2-pyrimidinamine                                51                                                                               Ex. 1   4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-4-(3-pyridinyl)-                                                         120-122.5                                   carbonate     2-pyrimidinamine                                       52                                                                               Ex. 11  4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-4-(2-pyridinyl)-                                                       148.5-149.5                                   carbonate     2-pyrimidinamine                                       53                                                                               Ex. 4   3-Methylphenylguanidine                                                                       .sub.--N--(3-Methylphenyl)-4-(2-thienyl)-                                                        112.5-114.5                                   carbonate     2-pyrimidinamine                                       54                                                                               Ex. 10  Phenylguanidine carbonate                                                                    4-(2-Furanyl)- .sub.--N--phenyl-2-pyrimidin-                                                      144-145                                                     amine                                                  55                                                                               Ex. 10  3-Methylphenylguanidine                                                                      4-(2-Furanyl)- .sub.--N--(3-methylphenyl)-                                                          98-99.5                                     carbonate     2-pyrimidinamine                                       56                                                                               Ex. 14  4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-4-(6-methyl-3-                                                         154-155                                       carbonate     pyridinyl)-2-pyrimidinamine                            57                                                                               Ex. 15  4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-6-methyl-4-(6-                                                         118-120                                       carbonate     methyl-3-pyridinyl)-2-pyrimidin-                                               amine                                                  58                                                                               Ex. 16  4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-4-pyrazinyl-2-                                                         157.5-159                                     carbonate     pyrimidinamine                                         59                                                                               Ex. 16  3-Methylphenylguanidine                                                                       .sub.--N--(3-Methylphenyl)-4-(4-pyrazinyl)-                                                      112.5-117                                     carbonate     2-pyrimidinamine                                       60                                                                               Ex. 3   2-Methylphenylguanidine                                                                       .sub.--N--(2-Methylphenyl)-4-pyrazinyl)-2-                                                         129-130.5                                   carbonate     pyrimidinamine                                         61                                                                               Ex. 3   3-Ethylphenylguanidine                                                                        .sub.--N--(3-Ethylphenyl)-4-(4-pyridinyl)-                                                       126-128                                       sulfate       2-pyrimidinamine                                       62                                                                               Ex. 3   2,5-Dimethylphenylguani-                                                                      .sub.--N--(2,5-Dimethylphenyl)-4-(4-pyri-                                                        131-134                                       dine carbonate                                                                               dinyl-2-pyrimidinamine                                 63                                                                               Ex. 3   2,3-Dimethylphenylguani-                                                                      .sub.--N--(2,3-Dimethylphenyl)-4-(4-pyri-                                                        121-123                                       dine carbonate                                                                               dinyl)-2-pyrimidinamine                                64                                                                               Ex. 17  3-Methylphenylguanidine                                                                       .sub.--N--(3-Methylphenyl)-4-(3-thienyl)-                                                        104.5-105.5                                   carbonate     2-pyrimidinamine                                       65                                                                               Ex. 11  2,5-Dimethylphenylguani-                                                                      .sub.--N--(2,5-Dimethylphenyl)-4-(2-pyri-                                                        139-142                                       dine carbonate                                                                               dinyl)-2-pyrimidinamine                                66                                                                               Ex. 3   3,5-Dimethylphenylguani-                                                                      .sub.--N--(3,5-Dimethylphenyl)-4-(4-pyri-                                                        183-185                                       dine carbonate                                                                               dinyl)-2-pyrimidinamine                                67                                                                               Ex. 3   1- .sub.--Naphthylguanidine                                                                   .sub.--N--1- .sub.--Naphthalenyl-4-(4-pyridinyl)                              -                  174-176                                       nitrate       2-pyrimidinamine                                       68                                                                               Ex. 11  3,5-Dimethylphenylguani-                                                                      .sub.--N--(3,5-Dimethylphenyl)-4-(2-                                                             114-119                                       dine hydrochloride                                                                           pyridinyl)-2-pyrimidinamine                            69                                                                               Ex. 11  1- .sub.--Naphthylguanidine                                                                   .sub.--N--1- .sub.--Naphthalenyl-4-(2-pyridinyl)                              -                  135-138                                       nitrate       2-pyrimidinamine                                       70                                                                               Ex. 3   2,4-Dimethylphenylguani-                                                                      .sub.--N--(2,4-Dimethylphenyl)-4-(4-pyri-                                                        116-118                                       dine carbonate                                                                               dinyl)-2-pyrimidinamine                                71                                                                               Ex. 3   2,4,6-Trimethylphenyl-                                                                       4-(4-Pyridinyl)- .sub.--N--(2,4,6-trimethyl-                                                      142-144                                       guanidine carbonate                                                                          phenyl)-2-pyrimidinamine                               72                                                                               Ex. 10  4-Methoxyphenylguanidine                                                                     4-(2-Furanyl)- .sub.--N--(4-methoxyphenyl)-                                                         155-158.5                                   carbonate     2-pyrimidinamine                                       73                                                                               Ex. 10  [3-(Trifluoromethyl)-                                                                        4-(2-Furanyl)- .sub.--N--[3-(trifluorometh-                                                       150-154                                       phenyl]guanidine carbonate                                                                   yl)phenyl]-2-pyrimidinamine                            74                                                                               Ex. 10  4-Fluorophenylguanidine                                                                       .sub.--N--(4-Fluorophenyl)-4-(2-furanyl)-                                                        150-152                                       carbonate     2-pyrimidinamine                                       75                                                                               Ex. 11   .sub.--N--Cyclopentylguanidine                                                               .sub.--N--Cyclopentyl-4-(2-pyridinyl)-2-                                                         106-109                                       sulfate       pyrimidinamine                                         76                                                                               Ex. 11  3,4-Dimethylphenylguani-                                                                      .sub.--N--(3,4-Dimethylphenyl)-4-(2-pyri-                                                          130-133.5                                   dine carbonate                                                                               dinyl)-2-pyrimidinamine                                77                                                                               Ex. 17  4-Methoxyphenylguanidine                                                                      .sub.--N--(4-Methoxyphenyl)-4-(3-thienyl)-                                                         158-160.5                                   carbonate     2-pyrimidinamine                                       78                                                                               Ex. 10  3-Ethylphenylguanidine                                                                        .sub.--N--(3-Ethylphenyl)-4-(2-furanyl)-2-                                                       95-98                                         sulfate       pyrimidinamine                                         79                                                                               Ex. 6   Phenylguanidine carbonate                                                                    4-(1H--Indol-3-yl)- .sub.--N--phenyl-2-                                                           188-190                                                     pyrimidinamine                                         80                                                                               Ex. 3   2-Methoxy-5-methylphenyl-                                                                     .sub.-- N--(2-Methoxy-5-methylphenyl)-4-(4-                                                        96-98.5                                     guanidine carbonate                                                                          pyridinyl)-2-pyrimidinamine                            81                                                                               Ex. 20  3-Methylphenylguanidine                                                                       .sub.--N--(3-Methylphenyl)-4-(1-methyl-1H--                                                      117-120                                       carbonate     pyrrol-2-yl)-2-pyrimidinamine                          82                                                                               Ex. 20  4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-4-(1-methyl-1H--                                                       89-91                                         carbonate     pyrrol-2-yl)-2-pyrimidinamine                          83                                                                               Ex. 20  Phenylguanidine carbonate                                                                    4-(1-Methyl-1H--pyrrol-2-yl)- .sub.--N--                                                          118-120                                                     phenyl-2-pyrimidinamine                                84                                                                               Ex. 4   3-Ethylphenylguanidine                                                                        .sub.--N--(3-Ethylphenyl)-4-(2-thienyl)-2-                                                       114-116                                       sulfate       pyrimidinamine                                         85                                                                               Ex. 17  3-Ethylphenylguanidine                                                                        .sub.--N--(3-Ethylphenyl)-4-(3-thienyl)-                                                         86-89                                         sulfate       2-pyrimidinamine                                       86                                                                               Ex. 6   3-Methylphenylguanidine                                                                      4-(1H--Indol-2-yl)- .sub.--N--(3-methylphen-                                                      164-167                                       carbonate     yl)-2-pyrimidinamine                                   87                                                                               Ex. 18  3-Methylphenylguanidine                                                                       .sub.--N--(3-Methylphenyl)-4-(4-quinolin-                                                        196-198                                       carbonate     yl)-2-pyrimidinamine                                   88                                                                               Ex. 18  Phenylguanidine carbonate                                                                     .sub.--N--Phenyl-4-(4-quinolinyl)-2-pyrimi-                                                      182-184                                                     dinamine                                               89                                                                               Ex. 18  4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-4-(4-quinolinyl)-                                                      176-178                                       carbonate     2-pyrimidinamine                                       90                                                                               Ex. 10  3,5-Dimethylphenylguani-                                                                      .sub.--N--(3,5-Dimethylphenyl)-4-(2-fur-                                                         126-129                                       dine hydrochloride                                                                           anyl)-2-pyrimidinamine                                 91                                                                               Ex. 4   3,5-Dimethylphenylguani-                                                                      .sub.--N--(3,5-Dimethylphenyl)-4-(2-thien-                                                       152-155                                       dine hydrochloride                                                                           yl)-2-pyrimidinamine                                   92                                                                               Ex. 3    .sub.--N--Methyl- .sub.--N--phenylguani-                                                     .sub.--N--Methyl- .sub.--N--phenyl-4-(4-pyridiny                              l)-                105-107                                       dine hydrochloride                                                                           2-pyrimidinamine                                       93                                                                               Ex. 3   2,4-Difluorophenylguani-                                                                      .sub.--N--(2,4-Difluorophenyl)-4-(4-pyri-                                                        172-174                                       dine hydrochloride                                                                           dinyl)-2-pyrimidinamine                                94                                                                               Ex. 1   2,4-Difluorophenylguani-                                                                      .sub.--N--(2,4-Difluorophenyl)-4-(3-pyri-                                                        163-165                                       dine hydrochloride                                                                           dinyl)-2-pyrimidinamine                                95                                                                               Ex. 7   3-Methylphenylguanidine                                                                       .sub.--N--(3-Methylphenyl)-4-(5-methyl-2-                                                        114-116                                       carbonate     thienyl)-2-pyrimidinamine                              96                                                                               Ex. 3   2,6-Difluorophenylguani-                                                                      .sub.--N--(2,6-Difluorophenyl)-4-(4-pyri-                                                        174-176                                       dine hydrochloride                                                                           dinyl)-2-pyrimidinamine                                97                                                                               Ex. 9   Phenylguanidine carbonate                                                                     .sub.--N--Phenyl-4-(1H--pyrrol-2-yl)-2-                                                          154-157                                                     pyrimidinamine                                         98                                                                               Ex. 1   4-Tert-butylphenylguani-                                                                      .sub.--N--ν-(1,1-Dimethylethyl)phenyl]-4-                                                     130-133                                       dine sulfate  (3-pyridinyl)-2-pyrimidinamine                         99                                                                               Ex. 1   2,6-Difluorophenylguani-                                                                      .sub.--N--(2,6-Difluorophenyl)-4-(3-pyri-                                                        163-166                                       dine hydrochloride                                                                           dinyl)-2-pyrimidinamine                               100                                                                               Ex. 7   3,5-Dimethylphenylguani-                                                                      .sub.--N--(3,5-Dimethylphenyl)-4-(5-methyl-                                                      133-135                                       dine hydrochloride                                                                           2-thienyl)-2-pyrimidinamine                           101                                                                               Ex. 7   4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-4-(5-methyl-2-                                                         123-125                                       carbonate     thienyl)-2-pyrimidinamine                             102                                                                               Ex. 11  3,4-Dimethylphenylguani-                                                                      .sub.--N--[(3,4-Dimethylphenyl)methyl]-4-                                                        158-160                                       dine hydrochloride                                                                           (2-pyridinyl)-2-pyrimidinamine                        103                                                                               Ex. 7   3,5-Dimethylphenylguani-                                                                      .sub.--N--(3,5-Dimethylphenyl)-4-(3-methyl-                                                      151-155                                       dine hydrochloride                                                                           2-thienyl)-2-pyrimidinamine                           104                                                                               Ex. 9   3-Methylphenylguanidine                                                                       .sub.--N--(3-Methylphenyl)-4-(1H--pyrrol-2-                                                      129-130                                       carbonate     yl)-2-pyrimidinamine                                  105                                                                               Ex. 8   3-Methylphenylguanidine                                                                      4-(5-Methyl-2-furanyl)- .sub.--N--(3-meth-                                                        119-121                                       carbonate     ylphenyl)-2-pyrimidinamine                            106                                                                               Ex. 21  Phenylguanidine carbonate                                                                    4-Methyl-6-(5-methyl-2-thienyl)- .sub.--N--                                                       133-135                                                     phenyl-2-pyrimidinamine                               107                                                                               Ex. 3   4-(Dimethylamino)phenyl-                                                                      .sub.--N--[4-(Dimethylamino)phenyl]-4-(4-                                                        164-166                                       guanidine dihydrochloride                                                                    pyridinyl)-2-pyrimidinamine                           108                                                                               Ex. 3   3-Methoxyphenylguanidine                                                                      .sub.--N--(3-Methoxyphenyl)-4-(4-pyri-                                                           159-160                                       hydrochloride dinyl)-2-pyrimidinamine                               109                                                                               Ex. 11  3-Methoxyphenylguanidine                                                                      .sub.--N--(3-Methoxyphenyl)-4-(2-pyridin-                                                        110-113                                       hydrochloride yl)-2-pyrimidinamine                                  110                                                                               Ex. 11  4-(Dimethylamino)phenyl-                                                                      .sub.--N--[4-(Dimethylamino)phenyl]-4-(2-                                                        171-174                                       guanidine dihydrochloride                                                                    pyridinyl)-2-pyrimidinamine                           111                                                                               Ex. 1   3-Methoxyphenylguanidine                                                                      .sub.--N--(3-Methoxyphenyl)-4-(3-pyridin-                                                        126-127                                       hydrochloride yl)-2-pyrimidinamine                                  112                                                                               Ex. 1   3,5-Dimethylphenylguani-                                                                      .sub.--N--(3,5-Dimethylphenyl)-4-(3-pyri-                                                        125-128                                       dine hydrochloride                                                                           dinyl)-2-pyrimidinamine                               113                                                                               Ex. 1   4-(Ethoxycarbonyl)phenyl-                                                                    4-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                               197-202                                       guanidine hydrochloride                                                                      amino]benzoic acid, ethyl ester                       114                                                                               Ex. 1   4-(Dimethylamino)phenyl-                                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-p                              yridinyl)-         165-166                                       quanidine dihydrochloride                                                                    2-pyrimidinyl]-1,4-benzenediamine                     115                                                                               Ex. 22  Phenylguanidine carbonate                                                                    4-(2,5-Dimethyl-3-furanyl)- .sub.--N--                                                            116-118                                                     phenyl-2-pyrimidinamine                               116                                                                               Ex. 17  4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-4-(3-thienyl)-2-                                                         151-152.5                                   carbonate     pyrimidinamine                                        117                                                                               Ex. 22  3-Methylphenylguanidine                                                                      4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(3-                                                         144-146                                       carbonate     methylphenyl)-2-pyrimidinamine                        118                                                                               Ex. 22  3,5-Dimethylphenylguani-                                                                     4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(3,5-                                                       149-152                                       dine hydrochloride                                                                           dimethylphenyl)-2-pyrimidinamine                      119                                                                               Ex. 22  4-Ethylphenylguanidine                                                                       4-(2,5-Dimethyl-3-furanyl)- .sub.--N--(4-                                                         93-96                                         carbonate     ethylphenyl)-2-pyrimidinamine                         120                                                                               Ex. 1   3-Dimethylaminophenyl-                                                                        .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-p                              yridinyl)-2-       123-125                                       guanidine dihydrochloride                                                                    pyrimidinyl]-1,3-benzenediamine                       121                                                                               Ex. 11  3-(Ethoxycarbonyl)phenyl-                                                                    3-[[4-(2-Pyridinyl)-2-pyrimidinyl[-                                                               156-158                                       guanidine hydrochloride                                                                      amino]benzoic acid, ethyl ester                       122                                                                               Ex. 11  3-(Dimethylamin0ophenyl-                                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-p                              yridinyl)-2-       109-111                                       guanidine dihydrochloride                                                                    pyrimidinyl]-1,3-benzenediamine                       123                                                                               Ex. 1   3-(Ethoxycarbonyl)phenyl-                                                                    3-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                                95-103                                       guanidine hydrochloride                                                                      amino]benzoic acid, ethyl ester                       124                                                                               Ex. 10  4-(Dimethylamino)phenyl-                                                                      .sub.--N'--[4-(2-Furanyl)-2-pyrimidinyl]-                                                        166-167                                       guanidine dihydrochloride                                                                     .sub.--N, .sub.--N--dimethyl-1,4-benzenediamine      125                                                                               Ex. 4   4-(Dimethylamino)phenyl-                                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-t                              hienyl)-2-         174-175                                       guanidine dihydrochloride                                                                    pyrimidinyl]-1,4-benzenediamine                       126                                                                               Ex. 22  4-(Dimethylamino)phenyl-                                                                      .sub.--N'--[4-(2,5-Dimethyl-3-furanyl)-2-                                                        126-129                                       guanidine dihydrochloride                                                                    pyrimidinyl]- .sub.--N, .sub.--N--dimethyl-1,4-                                benzenediamine                                        127                                                                               Ex. 19  4-(Dimethylamino)phenyl-                                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(3-m                              ethyl-2-           145-148                                       guanidine dihydrochloride                                                                    thienyl)-2-pyrimidinyl]-1,4-                                                   benzenediamine                                        128                                                                               Ex. 3   3-(Dimethylamino)phenyl-                                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-p                              yridinyl)-2-       165-168                                       guanidine dihydrochloride                                                                    pyrimidinyl]-1,3-benzenediamine                       129                                                                               Ex. 12  3,5-Dimethylphenylguani-                                                                      .sub.--N--(3,5-Dimethylphenyl)-4-(2-fur-                                                         155-158                                       dine          anyl)-5-methyl-2-pyrimidinamine                       130                                                                               Ex. 12  4-(Dimethylamino)phenyl-                                                                      .sub.--N'--[4-(2-Furanyl)-5-methyl-2-                                                            146-148                                       guanidine dihydrochloride                                                                    pyrimidinyl] .sub.--N, .sub.--N--dimethyl-1,4-                                 benzenediamine                                        131                                                                               Ex. 29  4-(Dimethylamino)phenyl-                                                                      .sub.--N'--[4-(2-Benzofuranyl)-2-pyrimi-                                                         175-178                                       guanidine dihydrochloride                                                                    dinyl]- .sub.--N, .sub.--N--dimethyl-1,4-benzene-                              diamine                                               132                                                                               Ex. 11  2-Guanidinobenzimidazole                                                                      .sub.--N--[4-(2-Pyridinyl)-2-pyrimidinyl]-                                                         276-279.5                                                 1H--benzimidazol-2-amine                              132                                                                               Ex. 23  Phenylguanidine carbonate                                                                    4-Methyl- .sub.--N--phenyl-6-(2-pyridinyl)-                                                       94-98                                                       2-pyrimidinamine                                      134                                                                               Ex. 4   3-(Dimethylamino)phenyl-                                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-t                              hienyl)-2-         118-120                                       guanidine dihydrochloride                                                                    pyrimidinyl]-1,3-benzenediamine                       135                                                                               Ex. 8   3-(Dimethylamino)phenyl-                                                                      .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(5-m                              ethyl-2-           126-129                                       quanidine dihydrochloride                                                                    furanyl)-2-pyrimidinyl]-1,3-ben-                                               zenediamine                                           136                                                                               Ex. 22  3-(Dimethylamino)phenyl-                                                                      .sub.--N'--[4-(2,5-Dimethyl-3-furanyl)-2-                                                        153-155                                       guanidine dihydrochloride                                                                    pyrimidinyl]- .sub.--N, .sub.--N--dimethyl-1,3-                                benzenediamine                                        137                                                                               Ex. 3   4-Aminoacetylphenylguani-                                                                     .sub.--N--[4-[[4-(Pyridinyl)-2-pyrimidin-                                                        294-296                                       dine hydrochloride                                                                           yl]amino]phenyl]acetamide                             138                                                                               Ex. 3   4-(Diethylamino)phenyl-                                                                       .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(4-py                              ridinyl)-          126-128                                       guanidine dihydrochloride                                                                    2-pyrimidinyl]-1,4-benzenediamine                     139                                                                               Ex. 1   4-(Diethylamino)phenyl-                                                                       .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(3-py                              ridinyl)-          100-104                                       guanidine dihydrochloride                                                                    2-pyrimidinyl]-1,4-benzenediamine                     140                                                                               Ex. 17  Phenylguanidine carbonate                                                                     .sub.--N--Phenyl-4-(3-thienyl)-2-pyrimidin-                                                      142-143                                                     amine                                                 141                                                                               Ex. 11  4-Fluorophenylguanidine                                                                       .sub.--N--(4-Fluorophenyl)-4-(2-pyridinyl)-                                                      207-209                                       carbonate     2-pyrimidinamine                                      142                                                                               Ex. 11  4-Chlorophenylguanidine                                                                       .sub.-- N--(4-Chlorophenyl)-4-(2-pyridinyl)-                                                     220-222                                       carbonate     2-pyrimidinamine                                      143                                                                               Ex. 3   4-Methylphenylguanidine                                                                       .sub.--N--(4-Methylphenyl)-4-(4-pyridinyl)-                                                      197.5-198.5                                   carbonate     2-pyrimidinamine                                      144                                                                               Ex. 31   .sub.--N--[3-(Trifluoromethyl)-                                                             4-(2-Phenothiazine)- .sub.--N--[3-(tri-                                                           240-243                                       phenyl]guanidine carbon-                                                                     fluoromethyl)phenyl]-2-pyrimidin-                                ate           amine                                                 145                                                                               Ex. 31  4-Methoxyphenylguanidine                                                                      .sub.--N--(4-Methoxyphenyl)-4-(2-pheno-                                                          220-225                                       carbonate     thiazine)-2-pyrimidinamine                            146                                                                               Ex. 31  3,4-Dichlorophenylguani-                                                                      .sub.--N--(3,4-Dichlorophenyl)-4-(2-pheno-                                                       235-238                                       dine carbonate                                                                               thiazine)-2-pyrimidinamine                            147                                                                               Ex. 11  2,4-Dimethylphenylguani-                                                                      .sub.--N--(2,4-Dimethylphenyl)-4-(2-pyri-                                                        111.5-113.5                                   dine carbonate                                                                               dinyl)-2-pyrimidinamine                               148                                                                               Ex. 3   2-Methoxyphenylguanidine                                                                      .sub.--N--(2-Methoxyphenyl)-4-(4-pyridin-                                                        112-117                                       carbonate     yl)-2-pyrimidinamine                                  149                                                                               Ex. 3   2,5-Dimethoxyphenylguani-                                                                     .sub.--N--(2,5-Dimethoxyphenyl)-4-(4-pyri-                                                       151.5-155.0                                   dine carbonate                                                                               dinyl)-2-pyrimidinamine                               150                                                                               Ex. 11  2-Methoxy-5-methylphenyl-                                                                     .sub.--N--(2-Methoxy-5-methylphenyl)-4-(2-                                                         117-118.5                                   guanidine carbonate                                                                          pyridinyl)-2-pyrimidinamine                           151                                                                               Ex. 3   3,4-Dimethylphenylguani-                                                                      .sub.--N--[(3,4-Dimethylphenyl)methyl]-4-                                                        132-136                                       dine hydrochloride                                                                           (4-pyridinyl)-2-pyrimidinamine                        152                                                                               Ex. 29  3-Methylphenylguanidine                                                                      4-(2-Benzofuranyl)- .sub.--N--(3-methyl-                                                          143-144                                       carbonate     phenyl)-2-pyrimidinamine                              153                                                                               Ex. 3   3,4-Dimethylphenylguani-                                                                      .sub.--N--(3,4-Dimethylphenyl)-4-(4-pyri-                                                          169-171.5                                   dine carbonate                                                                               dinyl)-2-pyrimidinamine                               154                                                                               Ex. 17  4-Fluorophenylguanidine                                                                       .sub.--N--(4-Fluorophenyl)-4-(3-thienyl)-                                                        185-187                                       carbonate     2-pyrimidinamine                                      155                                                                               Ex. 31  Phenylguanidine carbonate                                                                    4-(10H--Phenothiazin-2-yl)- .sub.--N--                                                            218-220                                                     phenyl-2-pyrimidinamine                               156                                                                               Ex. 6   4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-4-(1H--indol-3-                                                        209-210                                       carbonate     yl)-2-pyrimidinamine                                  157                                                                               Ex. 3   1,1'-Biphenylguanidine                                                                        .sub.--N--[1,1'-Biphenyl]-4-yl-4-(4-pyri-                                                        203-205                                       hydrochloride dinyl)-2-pyrimidinamine                               158                                                                               Ex. 3   [4-(1,1-Dimethylethyl)-                                                                       .sub.--N--[4-(1,1-Dimethylethyl)phenyl]-                                                         181-183                                       phenyl]guanidine sulfate                                                                     4-(4-pyridinyl)-2-pyrimidinamine                      159                                                                               Ex. 11   .sub.--N--Methyl- .sub.--N--phenylguani-                                                     .sub.--N--Methyl- .sub.--N--phenyl-4-(2-pyridiny                              l)-                88-91                                         dine hydrochloride                                                                           2-pyrimidinamine                                      160                                                                               Ex. 9   4-Ethylphenylguanidine                                                                        .sub.--N--(4-Ethylphenyl)-4-(1 .sub.--H--pyrrol-                              2-                 131-133                                       carbonate     yl)-2-pyrimidinamine                                  161                                                                               Ex. 19  Phenylguanidine carbonate                                                                    4-(3-Methyl-2-thienyl)- .sub.--N--phenyl-                                                         137-140                                                     2-pyrimidinamine                                      162                                                                               Ex. 25  4-Dimethylaminophenyl-                                                                        .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-meth                              yl-6-(4-           153-154                                       guanidine dihydrochloride                                                                    pyridinyl)-2-pyrimidinyl]-1,4-                                                 benzenediamine                                        163                                                                               Ex. 26  3,5-Dimethylphenylguani-                                                                      .sub.--N--(3,5-Dimethylphenyl)-4-methyl-6-                                                       136-140                                       dine hydrochloride                                                                           (3-pyridinyl)-2-pyrimidinamine                        164                                                                               Ex. 12   .sub.--N--[3-(Trifluoromethyl)-ate                                                          4-(2-Furanyl)-5-methyl- .sub.--N--[3-(tri-                                                        169-171                                       phenyl]guanidine carbon-                                                                     fluoromethyl)phenyl]-2-pyrimidin-                                              amine                                                 165                                                                               Ex. 23   .sub.--N--(3,5-Dimethylphenyl)-                                                              .sub.--N--(3,5-Dimethylphenyl)-4-methyl-6-                                                       110-112                                       guanidine     (2-pyridinyl)-2-pyrimidinamine                        166                                                                               Ex. 10  2-Guanidinobenzimidazole                                                                      .sub.--N--[4-(2-Furanyl)-2-pyrimidinyl]-                                                         306.5-308                                                   1H--benzimidzaol-2-amine                              167                                                                               Ex. 23   .sub.--N--[4-(Dimethylamino)-                                                                .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-meth                              yl-6-(2-           145-148                                       phenyl]guanidine dihydro-                                                                    pyridinyl)-2-pyrimidinyl]-1,4-                                   chloride      benzenediamine                                        168                                                                               Ex. 3   4-(1-Imidazolyl)phenyl-                                                                       .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)Phenyl]-                              4-                 >320                                          guanidine dihydrochloride                                                                    (4-pyridinyl)-2-pyrimidinamine                        169                                                                               Ex. 30  4-(1-Imidazolyl)phenyl-                                                                       .sub.--N--[4-(1 .sub.--H-Imidazol-1-yl)phenyl]-4                              -                  134-174                                       guanidine dihydrochloride                                                                    (3-pyridinyl)-2-pyrimidinamine                                                                    (Dec.)                             170                                                                               Ex. 11   .sub.--N--[4-Diethylamino)phen-                                                              .sub.--N, .sub.--N--Diethyl-n'-[4-(2-pyridinyl)-                              2-                 138-139                                       yl]guanidine dihydro-                                                                        pyrimidinyl]-1,4-benzenediamine                                  chloride                                                            171                                                                               Ex. 11  4-(1-Imidazolyl)phenyl-                                                                       .sub.--N--[4-(1 .sub.--H-Imidazol-1-yl)phenyl]-4                              -                  204-206                                       guanidine dihydrochloride                                                                    (2-pyridinyl)-2-pyrimidinamine                        172                                                                               Ex. 10  4-(1-Imidazolyl)phenyl-                                                                      4-(2-Furanyl)- .sub.--N--[4-(1 .sub.--H--imidazol                               -1-                 211-212.5                                   guanidine dihydrochloride                                                                    yl)phenyl]-2-pyrimidinamine                           173                                                                               Ex. 12   .sub.--N--[3-Dimethylamino)phen-                                                             .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-f                              uranyl)-5-         154-156                                       yl]guanidine dihydro-                                                                        methyl-2-pyrimidinyl]-1,3-benzene-                                                                154-156                                       chloride      diamine                                               174                                                                               Ex. 21   .sub.--N--[3-Dimethylamino)phen-                                                             .sub.--N, .sub.--N--Dimethyl- .sub.--N'-[4-(5-me                              thyl-2-            130-133                                       yl]guanidine dihydro-                                                                        thienyl)-2-pyrimidinyl]-1,3-ben-                                 chloride      zenediamine                                           175                                                                               Ex. 17   .sub.--N--[4-(Dimethylamino)-                                                                .sub.--N, .sub.--N--Dimethyl-n'-[4-(3-thienyl)-2                              -                  173-174                                       phenyl]guanidine dihydro-                                                                    pyrimidinyl]-1,4-benzenediamine                                  chloride                                                            176                                                                               Ex. 13   .sub.--N--[3-Dimethylamino)phen-                                                             .sub.--N, .sub.--N--Dimethyl- .sub.--N'-]4-methy                              l-6-(4-            200-201                                       yl]guanidine dihydro-                                                                        pyridiny)-2-pyrimidinyl]-1,3-                                    chloride      benzenediamine                                        177                                                                               Ex. 4   4-(1-Imidazolyl)phenyl-                                                                       .sub.--N--[4-(1 .sub.--H-Imidazol-1-yl)phenyl]-4                              -                  179-189                                       guanidine hydrochloride                                                                      (2-thienyl)-2-pyrimidinamine                                                                      (Dec.)                             178                                                                               Ex. 19   .sub.--N--(3-Methoxyphenyl)guani-                                                            .sub.--N--(3-Methoxyphenyl)-4-(3-methyl-2-                                                       120-123                                       dine hydrochloride                                                                           thienyl)-2-pyrimidinamine                             179                                                                               Ex. 30   .sub.--N--[4-(Acetylamino)phen-                                                              .sub.--N--[4-[[4-(3-Pyridinyl)-2-pyrimidin-                                                      192-195                                       yl]guanidine hydrochloride                                                                   yl]amino]phenyl]acetamide                             180                                                                               Ex. 30   .sub.--N--(4-Benzenesulfonamido)-                                                           4-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                               224-225                                       guanidine hydrochloride                                                                      amino]benzenesulfonamide                              181                                                                               Ex. 3    .sub.--N--(3-Chlorophenyl)guani-                                                             .sub. --N--(3-Chlorophenyl)-4-(4-pyridinyl)-                                                     160-161                                       dine carbonate                                                                               2-pyrimidinamine                                      182                                                                               Ex. 30   .sub.--N--(3-Chlorophenyl)guani-                                                             .sub.--N--(3-Chlorophenyl)-4-(3-pyridinyl)-                                                      146-148                                       dine carbonate                                                                               2-pyrimidinamine                                      183                                                                               Ex. 17   .sub.--N--(3-Methoxyphenyl)guani-                                                            .sub.--N--(3-Methoxyphenyl)-4-(3-thienyl)-                                                       142-145                                       dine hydrochloride                                                                           2-pyrimidinamine                                      184                                                                               Ex. 4    .sub.--N--(3-Methoxyphenyl)guani-                                                            .sub.--N--(3-Methoxyphenyl)-4-(2-thienyl)-                                                       151-153                                       dine hydrochloride                                                                           2-pyrimidinamine                                      185                                                                               Ex. 30   .sub.--N--Methyl- .sub.--N--acteylphenyl-                                                    .sub.--N--Methyl- .sub.--N--[4-[[4-(3-pyridinyl)                              -2-                194-197                                       guanidine hydrochloride                                                                      pyrimidinyl]amino]phenyl]acetamide                    186                                                                               Ex. 3    .sub.--N--Methyl- .sub.--N--acetylphenyl-                                                    .sub.--N--Methyl-n--[4-[[4-pyridinyl)-2-                                                         233-234                                       guanidine hydrochloride                                                                      pyrimidinyl]amino]phenyl]acetamide                    187                                                                               Ex. 11   .sub.--N--Methyl- .sub.--N--acetylphenyl-                                                    .sub.--N--Methyl- .sub.--N--[4-[[4-(2-pyridinyl)                              -2-                179-181                                       guanidine hydrochloride                                                                      pyrimidinyl]amino]phenyl]acetamide                    188                                                                               Ex. 10   .sub.--N--(3-Methoxyphenyl)guani-                                                           4-(2-Furanyl)- .sub.--N--(3-methoxyphenyl)-                                                       114-116                                       dine hydrochloride                                                                           2-pyrimidinamine                                      189                                                                               Ex. 29   .sub.--N--(3-Methoxyphenyl)guani-                                                           4-(2-Benzofuranyl)- .sub.--N--(3-methoxy-                                                         137                                           dine hydrochloride                                                                           phenyl)-2-pyrimidinamine                              190                                                                               Ex. 9    .sub.--N--(Ethylphenyl)guanidine                                                             .sub.--N--(4-Ethylphenyl)-4-(1-methyl-1H--                                                       89-91                                         carbonate     pyrrol-2-yl)-2-pyrimidinamine                         191                                                                               Ex. 3    .sub.--N--Acetylphenylguanidine                                                              .sub.--N--[4-[[4-(4-Pyridinyl)-2-pyrimi-                                                         294-296                                       hydrochloride dinyl]amino]phenyl]acetamide                          192                                                                               Ex. 10   .sub.--N, .sub.--N--Dimethylphenylguani-                                                     .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(2-f                              uranyl)-5-         154-156                                       dine dihydrochloride                                                                         methyl-2-pyrimidinyl]-1,3-benzene-                                             diamine                                               193                                                                               Ex. 30   .sub.--N--Acetylphenylguanidine                                                              .sub.--N--[4-[[4-(3-Pyridinyl)-2-pyrimidin-                                                      192-195                                       hydrochloride yl]amino]phenyl]acetamide                             194                                                                               Ex. 11  Sulfonylaminophenyl-                                                                         4-[[4-(2-Pyridinyl)-2-pyrimidinyl]-                                                               274-277                                       guanidine hydrochloride                                                                      amino]benzenesulfonamide                              195                                                                               Ex. 11    .sub.--N--Acetylphenylguanidine                                                             .sub.--N--[4-[[4-(2-Pyridinyl)-2-pyrimidin-                                                      254-255                                       hydrochloride yl]amino]phenyl]acetamide                             196                                                                               Ex. 4   3-Methoxyphenylguanidine                                                                      .sub.--N--(3-Methoxyphenyl)-4-(2-thienyl)-                                                       151-153                                       hydrochloride 2-pyrimidinamine                                      197                                                                               Ex. 30  4-(4-Methylpiperazin-1-                                                                       .sub.--N--[4-(4-Methyl-1-piperazinyl)-                                                           174-175                                       yl)phenylguanidine                                                                           phenyl]-4-(3-pyridinyl)-2-pyrimi-                                dihydrochloride                                                                              dinamine                                              198                                                                               Ex. 7   3-Methoxyphenylguanidine                                                                      .sub.--N--(3-Methoxyphenyl)-4-(5-methyl-2-                                                       149-151                                       hydrochloride thienyl)-2-pyrimidinamine                             199                                                                               Ex. 11  3-Chlorophenylguanidine                                                                       .sub.--N--(3-Chlorophenyl)-4-(2-pyridinyl)-                                                      164-165                                       hydrochloride 2-pyrimidinamine                                      200                                                                               Ex. 10  4-(4-Methylpiperazine-1-                                                                     4-(2-Furanyl)- .sub.--N--[4-(4-methyl-1-                                                          193-195                                       yl)phenylguanidine                                                                           piperazinyl)phenyl]-2-pyrimidin-                                 dihydrochloride                                                                              amine                                                 201                                                                               Ex. 4   4-(4-Methylpiperazin-1-                                                                       .sub.--N--[4-(4-Methyl-1-piperazinyl)-                                                           215.5-216.5                                   yl)phenylguanidine                                                                           phenyl]-4-(2-thienyl)-2-pyrimidin-                               dihydrochloride                                                                              amine                                                 202                                                                               Ex. 11  4-(4-Methylpiperazin-1-                                                                       .sub.--N--[4-(4-Methyl-1-piperazinyl)-                                                           192-193                                       yl)phenylguanidine                                                                           phenyl]-4-(2-pyridinyl)-2-pyrimi-                                dihydrochloride                                                                              dinamine                                              203                                                                               Ex. 13  4-(4-Methylpiperazin-1-                                                                       .sub.--N--[4-(4-Methyl-1-piperazinyl)-                                                           207-209                                       yl)phenylguanidine                                                                           phenyl]-4-(4-pyridinyl)-2-                                       dihydrochloride                                                                              pyrimidinamine                                        204                                                                               Ex. 22  3-Methoxyphenylguani-                                                                         .sub.-- N--(3-Methoxyphenyl)-4-(2,5-dimeth-                                                      124-125                                       dine hydrochloride                                                                           yl-3-furanyl)-2-pyrimidinamine                        205                                                                               Ex. 13  3-Fluorophenylguani-                                                                          .sub.--N--(3-Fluorophenyl)-4-(4-pyridinyl)-                                                      162                                           dine hydrochloride                                                                           2-pyrimidinamine                                      206                                                                               Ex. 30  3-Fluorophenylguani-                                                                          .sub.--N--(3-Fluorophenyl)-4-(3-pyridinyl)-                                                      147-150                                       dine hydrochloride                                                                           2-pyrimidinamine                                      207                                                                               Ex. 11  3-Fluorophenylguani-                                                                          .sub.--N--(3-Fluorophenyl)-4-(2-pyridinyl)-                                                      162-164                                       dine hydrochloride                                                                           2-pyrimidinamine                                      208                                                                               Ex. 30  4-Acetylphenylguani-                                                                         1-[3-[[4-(3-Pyridinyl)-2-pyrimi-                                                                  166-168                                       dine          dinyl]amino]phenyl]ethanone                           209                                                                               Ex. 30  1-(Methylethyl)phenyl-                                                                        .sub.--N--[4-(1-Methylethyl)phenyl]-4-(3-                                                        124-125                                       guanidine hydrochloride                                                                      pyridinyl)-2-pyrimidinamine                           210                                                                               Ex. 30  3-Ethylphenylguanidine                                                                        .sub.--N--(3-Ethylphenyl)-4-(3-pyridinyl)-                                                       80-88                                         hydrochloride 2-pyrimidinamine                                      211                                                                               Ex. 11  3-Ethylphenylguanidine                                                                        .sub.--N--(3-Ethylphenyl)-4-(2-pyridinyl)-                                                       101-104                                       hydrochloride 2-pyrimidinamine                                      212                                                                               Ex. 11  3-Benzenesulfonamido-                                                                        3-[[4-(2-Pyridinyl)-2-pyrimidinyl]-                                                               223-225                                       guanidine hydrochloride                                                                      amino]benzenesulfonamide                              213                                                                               Ex. 30  3-Benzenesulfonamido-                                                                        3-[[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                               278-280                                       guanidine hydrochloride                                                                      amino]benzenesulfonamide                              214                                                                               Ex. 24  4-(1,1-Dimethylethyl)-                                                                        .sub.--N--[4-(1,1-Dimethylethyl)phenyl]-4-                                                       150-154                                       phenylguanidine hydro-                                                                       (2-thienyl)-2-pyrimidinamine                                     chloride                                                            215                                                                               Ex. 10  4-(Diethylamino)phenyl-                                                                       .sub.--N, .sub. --N--Diethyl- .sub.--N'--[4-(2-f                              uranyl)-2-         132-133                                       guanidine hydrochloride                                                                      pyrimidinyl]-1,4-benzenediamine                       216                                                                               Ex. 13  4-Benzenesulfonamido-                                                                        3-[[4-(4-Pyridinyl)-2-pyrimidinyl]-                                                               265-264                                       guanidine hydrochloride                                                                      amino]benzenesulfonamide                              217                                                                               Ex. 13  4-Acetylaminophenyl-                                                                          .sub.--N--[3-[[4-(4-Pyridinyl)-2-pyrimi-                                                         267-270                                       guanidine hydrochloride                                                                      dinyl]amino]phenyl]acetamide                          218                                                                               Ex. 30  4-Acetylaminophenyl-                                                                          .sub.--N--[3-[[4-(3-Pyridinyl)-2-pyrimi-                                                         239-241                                       guanidine hydrochloride                                                                      dinyl]amino]phenyl]acetamide                          219                                                                               Ex. 11  3-Acetylaminophenyl-                                                                          .sub.--N--[3-[[4-(2-Pyridinyl)-2-pyrimi-                                                         190-192                                       guanidine hydrochloride                                                                      dinyl]amino]phenyl]acetamide                          220                                                                               Ex. 13  3-(1 .sub.--H--Imidazol-1-yl)-                                                                .sub.--N--[3-(1 .sub.--H--Imidazol-1-yl)phenyl]-                              4-                 232-234                                       phenylguanidine di-                                                                          (4-pyridinyl)-2-pyrimidinamine                                   hydrochloride                                                       221                                                                               Ex. 13  4-Acetylamino-3-methyl-                                                                       .sub.--N--[2-Methyl-4-[[4-(4-pyridinyl)-2-                                                       230-235                                       phenylguanidine hydro-                                                                       pyrimidinyl]amino]phenyl]acetamide                               chloride                                                            222                                                                               Ex. 21  4-Acetylaminophenyl-                                                                          .sub.--N--[4-[[4-(5-Methyl-2-thienyl)-2-                                                         227-230                                       guanidine hydrochloride                                                                      pyrimidinyl]amino]phenyl]acetamide                    223                                                                               Ex. 30  3-]2-(Diethylaminoeth-                                                                         .sub.--N--[3-[2-(Diethylamino)ethoxy]phen-                                                      79-82                                         oxy)phenyl]guanidine                                                                         yl]-4-(3-pyridinyl)-2-pyrimi-                                    dihydrochloride                                                                              dinamine                                              224                                                                               Ex. 30  2-Methoxyphenylguani-                                                                         .sub.--N--(2-Methoxyphenyl)-4-(3-pyridin-                                                         99-101                                       dine carbonate                                                                               yl0-2-pyrimidinamine                                  225                                                                               Ex. 24  4-Acetylaminophenyl-                                                                          .sub.--N--[4-[[4-(2-Thienyl)-2-pyrimidin-                                                        201-203                                       guanidine hydrochloride                                                                      yl]amino]phenyl]acetamide                             226                                                                               Ex. 30  4-Acetylamino-3-methyl-                                                                       .sub.--N--[2-Methyl-4-[4-(3-pyridinyl)-2-                                                        233-235                                       phenylguanidine hydro-                                                                       pyrimidinyl]acetamide                                            chloride                                                            227                                                                               Ex. 29  4-Diethylaminophenyl-                                                                         .sub.--N'--]4-(2-Benzofuranyl)-2-pyrimidin-                                                      134-136                                       guanidine hydrochloride                                                                      yl]- .sub.--N, .sub.--N--diethyl-1,4-benzenediami                              ne                                                    228                                                                               Ex. 12  4-Acetylaminophenyl-                                                                          .sub.--N--[4-[[4-(2-Furanyl)-2-pyrimidin-                                                        230-232                                       guanidine hydrochloride                                                                      yl]amino]phenyl]acetamide                             229                                                                               Ex. 13  4-(Imidazol-1-yl)-3-                                                                          .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)-3-(tri-                                                 238-239                                       (trifluoromethyl)phen-                                                                       fluoromethyl)phenyl]-4-(4-pyridin-                               ylguanidine dihydro-                                                                         yl)-2-pyrimidinamine                                             chloride                                                            230                                                                               Ex. 11  4-Acetylamino-3-methyl-                                                                       .sub.--N--[2-Methyl-4-[[4-(2-pyridinyl)-2-                                                       232-234                                       phenylguanidine hydro-                                                                       pyrimidinyl]amino]phenyl] acetamide                              chloride                                                            231                                                                               Ex. 30  3-(1-Imidazolyl)phenyl-                                                                       .sub.--N--[3-(1 .sub.--H-Imidazol-1-yl)phenyl]-4                              -                  137-144                                       guanidine dihydro-                                                                           (3-pyridinyl)-2-pyrimidinamine                                   chloride                                                            232                                                                               Ex. 24  3-(1-Imidazolyl)phenyl-                                                                       .sub.--N--[3-(1 .sub.--H-Imidazolyl)phenyl]-4-(2                              -                    183-184.5                                   guanidine dihydro-                                                                           thienyl)-2-pyrimidinamine                                        chloride                                                            233                                                                               Ex. 10  3-(1-Imidazolyl)phenyl-                                                                      4-(2-Furanyl)- .sub.--N--[3-(1 .sub.--H-imidazol-                              1-                 160-168                                       guanidine dihydro-                                                                           yl)phenyl]-2-pyrimidinamine                                      chloride                                                            234                                                                               Ex. 10  3-(Diethylamino)ethoxy-                                                                       .sub.--N--[3-[2-(Diethylamino)ethoxy]phen-                      phenylguanidine dihydro-                                                                     yl]-4-(2-furanyl)-2-pyrimidinamine                               chloride                                                            235                                                                               Ex. 10  3-Methylphenylguanidine                                                                      4-(2-Furanyl)- .sub.--N--(3-methylphenyl)-2-                                                      195-199                                       hydrochloride pyrimidinamine, hydrochloride                         236                                                                               Ex. 11  4-(1-Imidazolyl)-3-(tri-                                                                      .sub.--N--[4-(1 .sub.--H--Imidazol-1-yl)-3-(tri-                              2                  216-218                                       fluoromethyl)phenyl-                                                                         fluoromethyl)phenyl]-4-(2-pyridin-                               guanidine dihydro-                                                                           yl)-2-pyrimidinamine                                             chloride                                                            237                                                                               Ex. 24  3-(Diethylamino)ethoxy-                                                                       .sub.--N--[3-[2-(Diethylamino)ethoxy]phen-                      phenylguanidine di-                                                                          yl]-4-(2-thienyl)-2-pyrimidinamine                               hydrochloride                                                       238                                                                               Ex. 10  4-Benzenesulfonamido-                                                                        4-[[4-(2-Furanyl)-2-pyrimidinyl]-                                                                 255-257                                       guanidine hydrochloride                                                                      amino]benzenesulfonamide                              239                                                                               Ex. 21  4-Benzenesulfonamido-                                                                        4-[[4-(5-Methyl-2-thienyl)-2-                                                                     241-245                                       guanidine hydrochloride                                                                      pyrimidinyl]amino]benzenesul-                                                  fonamide                                              240                                                                               Ex. 17   .sub.--N--Methylacetylamino-                                                                 .sub.--N--Methyl- .sub.--N--[4-]]4-(3-thienyl)-2                              -                  150-153                                       phenylguanidine hydro-                                                                       pyrimidinyl]amino]phenyl]acetamide                               chloride                                                            241                                                                               Ex. 13  3-[4-Methyl-1-pipera-                                                                         .sub.--N--[3-(4-Methyl-1-piperazinyl)phen-                                                         150-151.5                                   zinyl]phenylguanidine                                                                        yl]-4(4-pyridinyl)-2-pyrimidina-                                 hydrochloride mine                                                  242                                                                               Ex. 10  3-[4-Methyl-1-pipera-                                                                        4-(2-Furanyl)- .sub.--N--[3-(4-methyl-1-                                                          134.5-136                                     zinyl]phenylguanidine                                                                        piperazinyl)phenyl]-2-pyrimidina-                                hydrochloride mine                                                  243                                                                               Ex. 24  3-[4-Methyl-1-pipera-                                                                         .sub.--N--[3-(4-Methyl-1-piperazinyl)phen-                                                         125-126.5                                   zinyl]phenylguanidine                                                                        yl]-4-(2-thienyl)-2-pyrimidinamine                               hydrochloride                                                       244                                                                               Ex. 13  2-Dimethylaminopheny-                                                                         .sub.--N, .sub.--N--Dimethyl- .sub.--N'--[4-(4-p                              yridinyl)-2-       114-119                                       guanidine dihydro-                                                                           pyrimidinyl]-1,2-benzenediamine                       245                                                                               Ex. 13  3-(Diethylamino)ethoxy-                                                                       .sub.--N--[3-[2-(Diethylamino)ethoxy]phen-                                                       100-103                                       phenylguanidine di-                                                                          yl]-4-(4-pyridinyl)-2-pyrimidina-                                hydrochloride mine                                                  246                                                                               Ex. 24  3-(Diethylamino)ethoxy-                                                                       .sub.--N--[4-[2-(Diethylamino)ethoxy]phen-                      phenylguanidine di-                                                                          yl]-4-(2-thienyl)-2-pyrimidinamine                               hydrochloride                                                       247                                                                               Ex. 24  3-(Dimethylamino)ethoxy-                                                                      .sub.--N--[4-[2-(Dimethylamino)ethoxy]phen-                                                      96-98                                         phenylguanidine di-                                                                          yl]-4-(2-thienyl)-2-pyrimidinamine                               hydrochloride                                                       248                                                                               Ex. 17  3-(Dimethylamino)ethoxy-                                                                      .sub.--N--[4-[2-(Dimethylamino)ethoxy]phen-                                                      83-85                                         phenylguanidine di-                                                                          yl]-4-(3-thienyl)-2-pyrimidinamine                               hydrochloride                                                       249                                                                               Ex. 21  4-Diethylaminophenyl-                                                                         .sub.--N, .sub.--N--Diethyl- .sub.--N'--[4-(5-me                              thyl-2-fur-        118-119                                       guanidine hydrochloride                                                                      anyl)-2-pyrimidinyl]-1,4-benzene-                                              diamine                                               250                                                                               Ex. 21  3-Methoxyphenylguani-                                                                         .sub.--N--(3-Methoxyphenyl)-4-(5-methyl-2-                                                       --                                            dine hydrochloride                                                                           furanyl)-2-pyrimidinamine                             251                                                                               Ex. 13  3-(1 .sub.--H-Imidazol-1-yl)-                                                                 .sub.--N--[3-(1 .sub.--H-Imidazol-1-yl)phenyl]-4                              -                  232-239                                       phenylguanidine di-                                                 (4-pyridinyl)-2-pyrimidinamine                                                            hydrochloride                                                       __________________________________________________________________________

EXAMPLE 252 1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone, oxime

A 2.03 mg portion of N-(4-acetylphenyl)-4-(3-pyridinyl)-2-pyrimidinamine was mixed with 210 ml of absolute ethanol and 1.26 g of hydroxylamine hydrochloride. An 18.2 ml portion of 1N sodium hydroxide was added, the mixture was heated at reflux for 2 hours and then evaporated to 1/4 volume. This was cooled, the solid collected, washed with ethanol and water and dried, giving 1.9 g of the desired product as cream colored crystals, mp 239°-241° C.

EXAMPLE 253 1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone, O-methyloxime

The procedure of Example 252 was repeated using methoxyamine hydrochloride, giving 1.78 g of the desired product as yellow crystals, mp 163°-167° C.

EXAMPLE 254 N-[1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyl]ethyl]formamide

A mixture of 7.25 g of N-(4-acetylphenyl)-4-(3-pyridinyl)-2-pyrimidinamine, 100 ml of formamide and 31 ml, of 98% formic acid was refluxed with stirring overnight. The solvents were then boiled off for 1/2 hour, the reaction cooled and poured into one liter of water. This was extracted with 725 ml of chloroform. The chloroform extract was back washed with 150 ml of water, then dried, filtered and evaporated to a foam. The foam was partitioned between chloroform and water. An equal volume of saturated potassium bicarbonate was added. The organic phase was separated, dried, filtered and evaporated to a foam. This foam was chromatographed on silica gel topped with a thin layer of hydrous magnesium silicate and eluted with chloroform (first four fractions), then with 2% methanol in chloroform (last two fractions). The sixth (final) fraction was evaporated and then crystallized from chloroform-hexane, giving 1.05 g of the desired product as cream colored crystals, mp 118°-121° C.

EXAMPLE 255 N-[4-[2-(Dimethylamino)ethoxy]phenyl]-4-(3-pyridinyl)-2-pyrimidinamine

A 1.10 g portion of dry 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol was dissolved in 25 ml of dimethylformamide. A 213 mg portion of sodium hydride (50% in oil) was added, the reaction was sealed and stirred for 45 minutes. A 480 mg portion of 2-dimethylaminoethyl chloride in 2 ml of dimethylformamide was added and the sealed mixture was stirred overnight. The solvent was removed at 60° C. and the residue partitioned between 25 ml of water and 50 ml of ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with 1N sodium hydroxide, dried, filtered and evaporated. The residue was taken up in 20 ml of chloroform, boiled down to 1/3 volume and hexane added to turbidity. The mixture was allowed to stand overnight, giving 400 mg of the desired product as beige crystals, mp 108°-110° C.

EXAMPLE 256 N-[4-[3 -(Dimethylamino)propoxy]phenyl]-4-(3-pyridinyl)-2-pyrimidinamine

A 5.46 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol was reacted with 3-dimethylaminopropyl chloride by the procedure of Example 255, giving 2.9 g of the desired product, mp 85°-87° C.

EXAMPLE 257 N-[4-[2-(Diethylamino)ethoxy]phenyl]-4-(4-pyridinyl)-2-pyrimidinamine

The procedure of Example 256 was repeated using 4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenol, giving 300 mg of the desired product as yellow crystals, mp 85°-87° C.

EXAMPLE 258 N-[4-[2-(Diethylamino)ethoxy]phenyl]-4-(3-pyridinyl)-2-pyrimidinamine

The procedured of Example 255 was repeated, using 2-diethylaminoethyl chloride, giving 3.45 g of the desired product as yellow crystals, mp 87°-89° C.

EXAMPLE 259 N-[4-[2-(Dimethylamino)ethoxy]phenyl]-4-(4-pyridinyl)-2-pyrimidinamine

The procedure of Example 255 was repeated using 4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenol, giving 1.6 g of the desired product as yellow crystals, mp 120°-122° C.

EXAMPLE 260 N-[4-[2-(Dimethylamino)ethoxy]phenyl]-N',N'-dimethyl-N-[4-(4-pyridinyl)-2-pyrimidinyl]-1,2-ethanediamine

The procedure of Example 259 was repeated. Subsequent crops of crystals gave 0.4 g of the desired product, mp 87°-91° C.

EXAMPLE 261 N-[4-[3-(Dimethylamino)propoxy]phenyl]-4-(4-pyridinyl)-2-pyrimidinamine

A 2.78 g portion of 4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenol and 2.35 g of 3-dimethylaminopropyl chloride was reacted as described in Example 255, giving 850 mg of the desired product, mp 123°-124.5° C.

EXAMPLE 262 [4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]phenoxy]acetic acid, ethyl ester

A mixture of 5.58 g of 4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenol was reacted with ethyl bromo acetate as described in Example 255, giving 1.8 g of the desired product as yellow crystals, mp 109°-111° C.

EXAMPLE 263 N-(4-Methoxyphenyl)-N-methyl-4-(3-pyridinyl)-2-pyrimidinamine

A 2.78 g portion of N-(4-methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinamine was dissolved in 30 ml of dimethylformamide. A 528 mg portion of sodium hydride (50% in oil) was added, the reaction sealed and stirred for 45 minutes. A solution of 1.70 g of methyl iodide in 2 ml of dimethylformamide was added, the sealed mixture was stirred overnight and the solvent removed. The residue was partitioned between water and chloroform. The organic phase was dried, filtered and evaporated. The residue was crystallized from ether-hexane giving 1.4 g of the desired product as yellow crystals, mp 88°-90° C.

EXAMPLE 264 N-(4-Methoxyphenyl)-N-methyl-4-(4-pyridinyl)-2-pyrimidinamine

The procedure of Example 263 was repeated using N-(4-methoxyphenyl)-4-(4-pyridinyl)-2-pyrimidinamine, giving 510 mg of the desired product as yellow crystals, mp 124°-126° C.

EXAMPLE 265 N-[2-(Diethylamino)ethyl]-4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide

A 1.55 ml portion of diethylethylenediamine was added to a solution of 0.01 mole of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid chloride in 50 ml of 1,2-dimethoxyethane. A 10 ml portion of triethylamine was added and the mixture was stirred for 2 hours. The solid was collected, washed with water and recrystallized from absolute ethanol, giving 1.22 g of the desired product, mp 148°-150° C.

EXAMPLE 266 N-Methyl-4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide

A 5.85 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid in 30 ml of thionyl chloride was refluxed on a steam bath for one hour, then evaporated to dryness. The residue was boiled with dimethoxyethane, then cooled and the solid recovered and washed with ether, giving 6.90 g of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid chloride.

A 6.03 g portion of the above acid chloride was suspended in 25 ml of ethanol and 10 ml of 25% aqueous methyl amine was added. The resulting solid was collected, taken up in hot 2-methoxyethanol, cooled and the solid collected, giving 3.35 g of the desired product, mp 254°-257° C.

EXAMPLE 267 4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]benzoic acid

To a solution of 19.89 g of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid, ethyl ester in 200 ml of 3A ethanol was added 12.5 ml of 10N sodium hydroxide. This mixture was refluxed on a steam bath for 3 hours and then allowed to evaporate. The residue was taken up in water and treated with 10.4 ml of concentrated hydrochloric acid. The resulting solid was collected and dried, giving 18.11 g of the desired product, mp 311°-317° C.

EXAMPLE 268 [4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]phenoxy]acetic acid

An 800 mg portion of [4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenoxy]acetic acid, ethyl ester was dissolved in 100 ml of ethanol and 10.7 ml of 1N sodium hydroxide was added. The mixture was stirred for 2 hours, the solvent removed and the residue dissolved in 5 ml of water. The pH was adjusted to 7.0 with 1N hydrochloric acid and the solid collected, washed with water and dried. The solid was recrystallized from dimethylformamide-ethanol, giving 600 mg of the desired product as yellow crystals, mp 308°-310° C.

EXAMPLE 269 4-[2-[(4-Methoxyphenyl)amino]-4-pyrimidinyl]-1-methylpyridinium iodide

A 2.0 g portion of N-(4-methoxyphenyl)-4-(4-pyridinyl-2-pyrimidinamine was dissolved in 550 ml of absolute ethanol and filtered. To this was added 10 ml of iodomethane. The reaction was heated on a steam bath for 4 hours. Another 10 ml of iodomethane was added and refluxing was continued overnight. The mixture was cooled, the solid collected, washed with ethanol and dried, giving 2.2 g of the desired product as purple crystals, mp 282°-284° C.

EXAMPLE 270 4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenol

A 25.0 g portion of N-(4-methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinamine was dissolved in 200 ml of 48% hydrobromic acid and stirred overnight under an argon atmosphere. The mixture was then heated on a steam bath for 7 hours, cooled overnight and evaporated at 60° C. The residue was basified with 200 ml of saturated potassium bicarbonate solution and stirred for 1.5 hours. The solid was collected, washed with water, dried and recrystallized from hot absolute ethanol, giving 19.1 g of the desired product, mp 223°-225° C.

EXAMPLE 271 4-[[4-(4-Pyridinyl)-2-pyrimidinyl]amino]phenol

The procedure of Example 270 was repeated using N-(4-methoxyphenyl)-4-(4-pyridinyl)-2-pyrimidinamine, giving 3.0 g of the desired product as yellow crystals, mp 268°-270° C.

EXAMPLE 272 N-[4-(2-Propenyloxy)phenyl]-4-(3-pyridinyl)-2-pyrimidinamine

A 2.73 g portion of dry 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol was dissolved in 50 ml of dry dimethylformamide. A 528 mg portion of sodium hydride (50% in oil) was added, the reaction was sealed and stirred for 45 minutes. A solution of 1.33 g of allyl bromide in 10 ml of dimethylformamide was added, the sealed mixture was stirred overnight and then evaporated at 80° C. The residue was partitioned between water and chloroform. The organic phase was separated, dried and filtered. The filtrate was evaporated and the residue crystallized from chloroform-hexane, giving 1.7 g of the desired product as yellow crystals, mp 105°-108° C.

EXAMPLE 273 N-(4-Ethylphenyl)-4-(4-pyridinyl)-2-pyrimidinamine, pyridine-1-oxide

A mixture of 2.76 g of N-(4-ethylphenyl)-4-(4-pyridinyl)-2-pyrimidinamine and 3.45 g of m-chloroperbenzoic acid in 100 ml of dichloromethane was stirred at room temperature for 20 hours. The mixture was washed three times with an aqueous saturated solution of sodium bicarbonate and a small amount of saturated saline. The organic layer was dried over magnesium sulfate, filtered through diatomaceous earth, then evaporated in vacuo to give a gelatenous solid. The solid was slurried with 50 ml of dichloromethane and filtered. The solid was washed with a small amount of dichloromethane and air dried to give 500 mg of the product. Recrystallization from absolute methanol gave 460 mg of the desired product, mp 223°-225° C.

EXAMPLE 274 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, dihydrochloride

A 2.0 g amount of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine was dissolved in 70 ml of dichloromethane with warming. The solution was cooled to room temperature, then hydrogen chloride gas was bubbled in to give a brick red precipitate. The mixture became very thick and more dichloromethane was added. The precipitate was collected, air dried, then dried in vacuo and gave 2.63 g of the desired product as red-orange crystals, mp 259°-262° C.

EXAMPLE 275 N-[4-(4-Pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine, hydrochloride

A 2.85 g amount of N-[4-[[4-(4-pyridinyl)-2-pyrimidinyl]amino]phenyl]acetamide was added to a mixture of 10 ml of concentrated hydrochloric acid and 10 ml of water. The reaction mixture was heated at reflux for 90 minutes, then evaporated in vacuo to obtain a solid. The solid was recrystallized from 3A ethanol/water and gave 2.31 g of the desired product as a yellow crystalline solid, mp 292°-295° C.

Additional hydrochloride salts listed in Examples 276 to 287 in Table V were obtained from the corresponding base compound by following procedures similar to those described in Examples 274 and 275 and employing various other solvents such as isopropyl alcohol, ethanol, ether and the like.

                  TABLE V                                                          ______________________________________                                         Ex   Compound                  MP °C.                                   ______________________________________                                         276  4-(3-Pyridinyl)- --N--[3-trifluoromethyl)-                                                               220-223                                              phenyl]pyrimidinamine, hydrochloride                                      277   --N, --N--Dimethyl- --N'--[4-(3-pyridinyl)-2-pyrim-                                                     239-245                                              idinyl]-1,4-benzenediamine, trihydrochloride                              278   --N--[4-[2-(Diethylamino)ethoxy]phenyl]-4-                                                              115-150                                              (3-pyridinyl)-2-pyrimidinamine, hydrochlo-                                                               (dec)                                                ride                                                                      279   --N, --N--Dimethyl- --N'--[4-(2-pyridinyl)-2-(pyrimi-                                                   204-213                                              dinyl)]-1,3-benzenediamine, dihydrochloride                               280   --N, --N--Dimethyl- --N'--[4-(2-pyridinyl)-2-pyrimi-                                                    202-205                                              dinyl]-1,3-benzenediamine, trihydrochloride                               281   --N, --N--Dimethyl- --N'--[4-(4-pyridinyl)-2-pyrimi-                                                    178-184                                              dinyl]-1,3-benzenediamine, dihdrochloride                                 282   --N, --N--Dimethyl- --N'--[4-(2-pyridinyl)-2-pyrimi-                                                    229-234                                              dinyl]-1,4-benzenediamine, dihydrochloride                                283   --N, --N--Dimethyl- --N'--[4-(4-pyridinyl)-2-pyrimi-                                                    232-235                                              dinyl]-1,4-benzenediamine, trihydrochloride                               284   --N--[4-(1-Aminoethyl)phenyl]-4-(3-pyridinyl)-                                2-pyrimidinamine, trihydrochloride                                        285   --N--[3-(1 --H--Imidazol-1-yl)phenyl]-4-(2-pyri-                                                        232.5-234                                            dinyl)-2-pyrimidinamine, hydrochloride                                    286   --N--[3-(1 --H--Imidazol-1-yl)phenyl]-4-(4-pyri-                                                        259-266                                              dinyl)-2-pyrimidinamine, hydrochloride                                    287  4-(2-Furanyl)- --N--[3-(4-methyl-1-piperazin-                                                            259-263                                              yl)phenyl]-2-pyrimidinamine, hydrochloride                                ______________________________________                                    

EXAMPLE 288 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, sulfate

A 2.48 g amount of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine was dissolved in 120 ml of absolute ethanol with heating, then a solution of 1.02 g of concentrated sulfuric acid in 25 ml of ethanol was added dropwise with stirring. The mixture turned orange then a yellow precipitate formed. The mixture was chilled, the preciptate was collected, by filtration, washed with cold ethanol then with ether, and air dried to give 2.73 g of yellow-orange crystals.

The preceding compound was dissolved in a small amount of water, then a saturated aqueous solution of sodium bicarbonate was added to pH 8.0 to yield a light yellow precipitate. The precipitate was collected, washed with water and dried in vacuo. A 2.25 g portion this material was recrystallized from about 200 ml of absolute methanol in the cold. The product was collected, washed with absolute ethanol and dried in vacuo to give 1.75 g of the desired product as orange cyrstals, mp 233°-235° C.

Additional sulfate salts which were prepared from the corresponding base compound in the manner described hereinabove are listed as Examples 289 to 300 in Table VI.

                  TABLE VI                                                         ______________________________________                                         Ex   Compound                  MP °C.                                   ______________________________________                                         289  4-(2-Pyridinyl)- --N--[3-trifluoromethyl)-                                                               208-211                                              phenyl]-2-pyrimidinamine, sulfate                                         290   --N--(3-Methylphenyl)-4-(2-thienyl)-2-pyrimi-                                                           207.5-210                                            dinamine, sulfate                                                         291  4-(2-Furanyl)- --N--(3-methylphenyl)-2-pyrimi-                                                           187-193                                              dinamine sulfate                                                          292  4-(4-Pyridinyl)- --N--[3-(trifluoromethyl)phen-                                                          250-253                                              yl)]-2-pyrimidinamine, sulfate                                            293   --N--(4-Methoxyphenyl)-4-(3-pyridinyl)-2-                                                               103-123                                              pyrimidinamine, sulfate                                                   294   --N--Phenyl-4-(3-pyridinyl)-2-pyrimidinamine,                                                           167-187                                              sulfate                                                                   295  4-(3-Pyridinyl)- --N--[3-trifluoromethyl)phen-                                                           196-199                                              yl]-2-pyrimidinamine, sulfate                                             296   --N--(3,5-Dimethylphenyl)-[4-(3-pyridinyl)-2-                                                           209-214                                              pyrimidinamine, sulfate                                                   297   --N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                            216-218                                              pyrimidinamine, sulfate                                                   298   --N--(3,5-Dimethylphenyl)-4-methyl-6-(5-methyl-                                                         232-234                                              2-thienyl)-2-pyrimidinamine, sulfate                                      299  4-(2-Furanyl)-5-methyl- --N--phenyl-2-pyrimi-                                                            140-144                                              dinamine, sulfate                                                         300   --N, --N--Dimethyl- --N'--[4-(4-pyridinyl)-2-pyrimi-                                                    204-211                                              dinyl]-1,3-benzenediamine, sulfate                                        ______________________________________                                    

EXAMPLE 301 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, phosphate

A 2.0 g amount of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine was dissolved in 100 ml of ethanol with heating. The solution was allowed to cool to room temperature, then a solution of 2.07 g of phosphoric acid in 25 ml of ethanol was added with stirring. The mixture was chilled for several hours, then the precipitate which formed was collected by filtration, washed twice with cold ethanol and dried in vacuo for 16 hours to give 3.43 g of the desired product as orange crystals, mp 210.5°-212.5° C.

Additional phosphate salts which were prepared from the corresponding base compound in the manner described hereinabove are listed as Examples 302 to 305 in Table VII.

                  TABLE VII                                                        ______________________________________                                         Ex   Compound                  MP °C.                                   ______________________________________                                         302   --N--(3,5-Dimethylphenyl)-4-(3-pyridinyl)-2-                                                            190-192                                              pyrimidinamine, phosphate                                                 303   --N--(4-Methoxyphenyl)-4-(3-pyridinyl)-2-                                                               185-188                                              pyrimidinamine, phosphate                                                 304   --N--Phenyl-4-(3-pyridinyl)-2-pyrimidinamine                                                            176-179                                              phosphate                                                                 305   --N--(3,5-Dimethylphenyl)-4-(2-pyridinyl)-2-                                                            199-202                                              pyrimidinamine, phosphate                                                 ______________________________________                                    

EXAMPLE 306 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, (Z)-2-butenedioate (1:1)

A mixture of 4.97 g of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine and 2.55 g of maleic acid was dissolved in hot 2-methoxyethanol. Cooling gave 4.15 g of the desired product as an orange crystalline solid, mp 211°-214° C.

EXAMPLE 307 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, dinitrate

A 2.0 g amount of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine was dissolved in 100 ml of ethanol with heating. The solution was allowed to cool to room temperature, then a solution of 1.5 ml of concentrated nitric acid in 25 ml of ethanol was added with stirring to give a red-orange precipitate. The mixture was allowed to stand 30 minutes at room temperature, then was chilled for several hours. The solid was collected, washed with cold absolute ethanol and air dried to give 2.80 g of the desired product as red-orange crystals, mp 167°-169° C. (dec.).

EXAMPLE 308 N-Phenyl-4-(4-pyridinyl)-2-pyrimidinamine, compound with 2-hydroxy-1,2,3-propanetricarboxylate (2:1)

A mixture of 4.97 of N-phenyl-4-(4-pyridinyl)-2-pyrimidinamine and 4.62 g of citric acid was dissolved in hot absolute ethanol. Cooling gave 6.14 g of the product of the example as a yellow crystalline solid, mp 155°-157° C.

EXAMPLE 309 Oxo[phenyl[4-(4-pytridinyl)-2-pyrimidinyl]amino]acetic acid, ethyl ester

A 4.08 g portion of 2-phenylamino-4-(4-pyridinyl)pyrimidine was dissolved in 20 ml of dimethylformamide. A 5 g portion of 50% sodium hydride in oil was added using 10 ml of dimethylformamide as a wash. When bubbling ceased, a solution of 2.23 ml of ethyl oxalyl chloride in 10 ml of dimethylformamide was added dropwise. Chloroform and aqueous 10% potassium bicarbonate were added. The organic layer was separated, dried, filtered and evaporated giving the desired product.

EXAMPLE 310 N-[4-(2-Pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine, dihydrochloride

A 12.86 g portion of N-[4-[[4-(2-pyridinyl)-2-pyrimidinyl]amino]phenyl]acetamide in a mixture of 40 ml of water and 40 ml of concentrated hydrochloric acid was refluxed for 30 minutes and then cooled. The solid was collected and dried, giving 10.84 g of the desired product, mp 285°-288° C.

Following the procedure of this Example, and using as starting materials the products of the indicated examples, the products of Examples 311-322 in Table VIII were derived.

                  TABLE VIII                                                       ______________________________________                                              Start-                                                                         ing                                                                            Mate-                                                                     Ex.  rial    Product                MP °C.                              ______________________________________                                         311  Ex.      --N--Methyl- --N'--[4-(3-pyridinyl)-2-                                                               164-166                                         185     pyrimidinyl]-1,4-benzenediamine                                   312  Ex.      --N--Methyl- --N'--[4-(2-pyridinyl)-2-                                                               110-112                                         187     pyrimidinyl]-1,4-benzenediamine                                   313  Ex.      --N--[4-(3-Pyridinyl)-2-pyrimidinyl]-                                                                279-284                                         218     1,3-benzenediamine, dihydrochloride                               314  Ex.      --N--[4-(4-Pyridinyl)-2-pyrimidinyl]-                                                                199-202                                         217     1,3-benzenediamine                                                315  Ex.     2-Methyl- --N--[4-(4-pyridinyl)-2-                                                                    297-304                                         221     pyrimidinyl]-1,4-benzenediamine,                                               dihydrochloride                                                   316  Ex.      --N--[4-(2-Pyridinyl)-2-pyrimidinyl]-                                                                153-156                                         219     1,3-benzenediamine                                                317  Ex.      --N--[3-(1-Aminomethyl)phenyl]-4-(3-                                                                 230(dec.)                                       182     pyridinyl)-2-pyrimidinamine                                       318  Ex.      --N--[4-(5-Methyl-2-thienyl)-2-pyrimi-                                                               284-287                                         222     dinyl]-1,4-benzenediamine, dihydro-                                            chloride                                                          319  Ex.      --N--[4-(2-Furanyl)-2-pyrimidinyl]-1,4-                                                              261-266                                         228     benzenediamine, dihydrochloride                                   320  Ex.     2-Methyl- -- N--[4-(3-pyridinyl)-2-pyrimi-                                                            176-178                                         226     dinyl]-1,4-benzenediamine                                         321  Ex.     2-Methyl- --N--[4-(2-pyridinyl)-2-pyrimi-                                                             196-198                                         230     dinyl]-1,4-benzenediamine                                         322  Ex.      --N--[4-(4-Pyridinyl)-2-pyrimidinyl]-                                                                192-193.5                                       191     1,4-benzenediamine                                                ______________________________________                                    

EXAMPLE 323 2-[1-[4-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyl]ethylidene]hydrazinecarboxamide

A 2.9 g portion of 1-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone was mixed with 1.23 g of semicarbazide hydrochloride in 200 ml of absolute ethanol and 1.10 ml of 10N sodium hydroxide was added. This mixture was refluxed overnight, then cooled to room temperature and the solid collected and washed with ethanol, water and ethanol. The solid was recrystallized from dimethylsulfoxide/ethanol, giving 2.9 g of the desired product, mp 256°-258° C.

EXAMPLE 324 N-[4-[2-[bis(1-Methylethyl)amino]ethoxy]phenyl]-4-(3-pyridinyl)-2-pyrimidinamine

A 2.64 g portion of 4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenol was dissolved in 60 ml of dimethylformamide by warming on a steam bath and then cooled. A 2.0 g portion of diisopropylaminoethyl chloride hydrochloride was added and dissolved with stirring. A 20 ml portion of 5N sodium hydroxide was added dropwise over 5 minutes, then 5 ml of water was added and the mixture was stirred for 20hours. The mixture was then heated on a steam bath for 30 minutes, allowed to stand 48 hours and then evaporated. The residual gum was purified by flash dry column chromatography on silica gel eluting fractions 1-3 with methanol and fractions 4-6 with 1% methanol in chloroform. Fractions 4-6 were combined and evaporated, giving 500 mg of the desired product.

EXAMPLE 325 α-Methyl-4-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzenemethanol

A 1.45 g portion of 1-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone was dissolved with stirring in 220 ml of ethanol. A 125 mg portion of sodium borohydride was added and stirring continued for 3 hours. A 63 mg portion of sodium borohydride was added and stirring continued overnight. A 2 ml portion of glacial acetic acid was added and the mixture evaporated. The solid was triturated with water, dried and recrystallized from 30 ml of ethanol giving 710 mg of the desired product, mp 145°-147° C.

EXAMPLE 326 N-[1-[3-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenyl]ethyl]formamide

A mixture of 2.9 g of 1-[3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]ethanone, 40 ml of formamide and 13 ml of concentrated formic acid was refluxed for 15 hours, then cooled and evaporated. The residue was partitioned between unsaturated aqueous potassium bicarbonate and chloroform. The organic phase was separated, dried, filtered and evaporated. The residue was chromatographed on silica gel, eluting 125 ml fractions, fractions 1-4 with chloroform and fractions 5-7 with 2% methanol in chloroform. Fractions 5-7 were combined and evaporated, giving 1.25 g of the desired product as a yellow foam.

EXAMPLE 327 2-[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]phenol

A mixture of 35 g of N-(2-methoxyphenyl)-4-(3-pyridinyl)-2-pyrimidinamine in 200 ml of 47% aqueous hydrobromic acid was refluxed for 7 hours and then evaporated. The residue was mixed with saturated aqueous potassium bicarbonate and allowed to stand overnight, then filtered. The filtrate was concentrated, giving 3.5 g of the desired compound, mp 166°-169° C.

EXAMPLE 328 N-[3-(1H-Imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2-pyrimidinamine

A solution of 250 ml of 2-acetylpyridine and 500 ml of N,N-dimethylformamide dimethyl acetal was heated on a steam bath for 6 hours. After concentrating the reaction solution under vacuum, 1 liter of hexane was added to the part crystalline residue. The product was collected as small crystalline particles which were washed with an additional liter of hexane. Air drying was followed by drying at 45° C. under vacuum, leaving 350.7 g of 3-dimethylamino-1-(2-pyridinyl)-2-propen-1-one.

A mixture of 289.0 g of imidazole, 292 g of potassium carbonate, 3 liters of dimethyl sulfoxide, and 300.0 g of 1-fluoro-3-nitrobenzene was stirred and heated for 25.5 hours between 105°-110° C. Then the reaction was poured into 6 liters of water and cooled in the refrigerator over the weekend. The crystalline product was collected and washed with 1 liter of water. Air drying gave 357.6 g of solid. The solid was taken up in 2.4 liters of ethyl acetate and the hot solution passed through hydrous magnesium silicate. After boiling the filtrate down to 1.5 liters, it was cooled to give a precipitate which was collected and washed with 200 ml of ethylacetate, to leave 151.7 g of off-white crystals. After evaporating the mother liquor to dryness, the residue was recrystallized from 350 ml of ethyl acetate to give 59.7 g more product. The mother liquor from the second fraction was evaporated and the residual material recrystallized twice from ethyl acetate to give 30.9 g more product. Total product, 242.3 g of 1-(3-nitrophenyl)-1H-imidazole.

In a Parr hydrogenation bottle was placed 75.00 g of 1-(3-nitrophenyl)-1H-imidazole, 0.70 g platinum oxide, and 250 ml of ethanol. Shaking of this mixture in a Parr hydrogenation apparatus was continued until no more hydrogen was taken up. This process was repeated with 76.33 g of the imidazole, 1.0 g of platinum oxide and 250 ml of ethanol and again with 90.4 g of the imidazole, 1.0 g of platinum oxide and 240 ml of ethanol, until a total of 241.63 g had been reduced. For each batch the catalyst was filtered off and the solvent was removed under vacuum; and then the residues were combined to give 207.2 g of gray crystalline amine. Next the amine was recrystallized from 530 ml of 2-propanol. After collecting the product, it was washed with 200 ml of 2-propanol, and dried, under vacuum, to give 156.4 g of 3-(1H-imidazol-1-yl)benzamine.

A solution of 43.3 g of hydrogen chloride in 290 ml of ethanol was added to 189.0 g of 3-(1H-imidazol-1-yl)benzamine in a 2 liter Erlenmeyer flask. Then 104.7 g of cyanamid was added. The mixture was cautiously warmed in a water bath to an internal temperature of 83° C. over 25 minutes. When no exotherm had been noted, the flask was placed inside the steam bath and heated for 2 hours. A final temperature of 97° C. was achieved. The resulting brown syrup which was [3-(1H-imidazol-1-yl)phenyl]quanidine, monohydrochloride, was used in the next reaction without further purification.

A mixture of 164 g of potassium carbonate, 209.1 g of 3-dimethylamino-1-(2-pyridyl)-2-propen-1-one, 1.187 mole of crude [3-(1H-imidazole-1-yl)phenyl]guanidine monohydrochloride, and 1 liter of methoxyethanol was stirred and heated under very gentle reflux. A dry-ice condenser filled with water was used to prevent plugging by the dimethylammonium carbonate which is given off by the reaction. The reaction was stopped after 26.5 hours and permitted to stand overnight. A heavy precipitate had formed which was collected as A and washed with 100 ml of ether. The filtrate was concentrated under vacuum as B. Both A and B were triturated with 1.5 liters of water. Then A was washed with 300-400 ml of ethanol, followed by 100 ml of ether to leave, on drying, 172.9 g of gray solid, mp 200°-202° C. Recrystallization of B from 150 ml of 2-propanol gave a black solid, C. Next, a classical fractional recrystallization was carried out using methoxyethanol as the solvent. In the final stages, a large amount of charcoal was added to remove color. In this fashion two main fractions were obtained D, 79.0 g of yellow crystals, mp 204.5°-205.5° C., and E, 18.05 g of yellow crystals, mp 204°-204.5° C. The yield of D plus E was 26% of the desired product.

EXAMPLE 329 1-(2-Chloroethoxy)-3-nitrobenzene

A mixture of 6.96 g. of m-nitrophenol, 100 ml. of 2-butanone, 6.9 g. of potassium carbonate, and 11.74 g. of 2 chloroethyl-tosylate was stirred and heated under reflux for 24 hours. After cooling to room temperature, the salts were filtered off and the filtrate concentrated under vacuum. The residue crystallized on seeding and was recrystallized from carbon tetrachloride to give 8.3 g. of product, m.p. 54.5°-57° C.

EXAMPLE 330 1-[2-(3-Nitrophenoxy)ethyl]-1H-imidazole

After dissolving 3.74 g. of imidazole in 60 ml. of dry N,N-dimethylformamide, 1.78 g. of 50% sodium hydride in oil was added. When the effervescence had stopped (circa 1 hr.), 7.35 g. of 1-(2-chloroethoxy)-3-nitrobenzene was added. After stirring overnight, the reaction was concentrated under vacuum. Water was added to the residue and the product was extracted into chloroform. The product was extracted out of the chloroform layer with dilute hydrochloric acid. Next, the aqueous acid layer was neutralized with potassium carbonate and the oily product extracted into chloroform. Upon drying the chloroform extract with sodium sulfate, it was concentrated under vacuum to an oil which crystallized on standing. Recrystallization from isopropyl acetate gave 6.12 g. of product as the monohydrate, m.p. 52.5°-55.5° C.

EXAMPLE 331 3-[2-(1H-Imidazol-1-yl)ethoxy]benzamine

Using a Parr hydrogenator, 5.00 g. of 1-[2-(3-nitrophenoxy)ethyl]-1H-imidozole in 100 ml. of ethanol and 0.2 g. of platinum oxide was hydrogenated until the hydrogen uptake stopped. The catalyst was filtered off and the filtrate concentrated under vacuum. Several recrystallizations from isopropyl acetate gave 2.8 g. of amine, m.p. 74°-76.5° C.

EXAMPLE 332 [3-[2-(1H-Imidazol-1-yl)ethoxy]phenyl]-guanidine Dihydrochloride

To a solution of 1.7 g. of hydrogen chloride in 50 ml. of ethanol was added 4.70 g. of 3-[2-(1H-imidazol-1-yl)ethoxy]benzamine in 10 ml. of ethanol. After concentration under vacuum a foam was obtained which gradually crystallized. Next 1.95 g. of cyanamid and 20 ml. of ethanol were added and the mixture heated cautiously, first in a water bath, then directly in a steam bath for a total of 5 hours. A light brown oily guanidine resulted, which was used without purification.

EXAMPLE 333 3-[2-(4-Morpholinyl)ethoxy]-benzenamine

N-[2-Chloroethyl]morpholine hydrochloride, 80 g., was partitioned between 5N sodium hydroxide and methylene chloride. After drying the organic layer over magnesium sulfate, the solvent was removed under reduced pressure to leave 65 g. of free amine.

To 36.01 g. of m-aminophenol dissolved in 325 ml. of N,N-dimethylformamide, 16.3 g. of 50% sodium hydride in oil was added. The reaction was stirred for 1 hour, until the effervescence stopped; then 57 g. of N-(2-chloroethyl)morpholine, from above, was added. After stirring overnight, the mixture was heated on a steam bath for 1/2 hr., then concentrated under vacuum. The residue was taken up in 300 ml. of 2N hydrochloric acid and washed twice with ether. After basifying with 10N sodium hydroxide, the product was extracted into ether, dried (magnesium sulfate), filtered through hydrous magnesium silicate and evaporated to a brown oil. Distillation gave 34.0 g. of a golden oil, b.p. 165°-180° C./0.45 mm.

EXAMPLE 334 [3-[2-(4-Morpholinyl)ethoxy]phenyl]guanidine monohydrochloride

Prepared from 3-[2-(4-morpholinyl)ethoxy]-benzamine by the method of Example 332.

EXAMPLE 335 1-(Bromoacetyl)-4-methylpiperazine monohydrochloride

A solution of 10.0 g. of 1-methyepiperazine in 150 ml of chloroform was cooled in a water bath while 17.3 g. of bromoacetyl chloride in 150 ml. of chloroform was added dropwise, with stirring, over 1/2 hour. A calcium chloride tube protected the reaction from moisture. After stirring overnight, the precipitate was collected and washed with chloroform. The crude product was dried under vacuum at 50° and used as such.

EXAMPLE 336 1-[(4-Aminophenoxy)acetyl]-4-methylpiperazine

Prepared from p-aminophenol and 1-(bromoacetyl)-4-methylpiperazine by the method of Example 333 to give a product of m.p. 71°-73° C.

EXAMPLE 337 1-[[4-[(Aminoiminomethyl)amino]phenoxy]acetyl]-4-methylpiperazine Dihydrochloride

Prepared from 1-[(4-aminophenoxy)acetyl]-4-methylpiperazine by the method of Example 332.

                  TABLE IX                                                         ______________________________________                                              Acry-                                                                          loyl    Phenylguanidine                                                   Ex.  Source  precurser     Product     Mp °C.                           ______________________________________                                         338  Ex. 11  [3-[2-(1H--Imidazol-                                                                         N--[3-[2-(1H--                                                                             149-                                                 1-yl)-ethoxy]-                                                                               Imidazol-1-yl)-                                                                            151.5                                                phenyl]guanidine                                                                             ethoxy]phenyl-                                                   dihydrochloride                                                                              4-(2-pyridinyl)                                                                2-pyrimidinamine                                    339  Ex. 13  [3-[2-(4-morpho-                                                                             N--[3-[2-(4-mor-                                                                           179-                                                 linyl)-ethoxy]-                                                                              pholinyl)-  181                                                  phenyl]guanidine                                                                             ethoxy]phenyl]-                                                  monohydrochloride                                                                            4-(4-pyridinyl)-                                                               2-pyrimidinamine                                    340  Ex. 24  [3-[2-(4-morpho-                                                                             N--[3-[2-(4-mor-                                                                           134-                                                 linyl)ethoxy]-                                                                               pholinyl)ethoxy]-                                                                          136                                                  phenyl]guanidine                                                                             phenyl]-4-(2-                                                    monohydrochloride                                                                            thienyl)-2-pyri-                                                               midinamine                                          341  Ex. 10  [3-[2-(4-morpho-                                                                             4-(2-furanyl)-N--                                                                          88-                                                  linyl)ethoxy]-                                                                               [3-[2-(4-morpho-                                                                           90                                                   phenyl]guanidine                                                                             linyl)ethoxy]-                                                   monohydrochloride                                                                            phenyl]-2-pyri-                                                                midinamine                                          342  Ex. 24  1-[[4-[(Aminoi-                                                                              1-Methyl-4-[[4-                                                                            173-                                                 minomethyl)amino]-                                                                           (2-thienyl)-2-                                                                             175                                                  phenoxy]acetyl]-4-                                                                           pyrimidinyl]-                                                    methyl piperazine                                                                            phenoxy]acetyl)-                                                 dihydrochloride                                                                              piperazine                                          343  Ex. 24  (4-chlorophenyl)                                                                             N--(4-chlorophe-                                                                           185-                                                 guanidine carbonate                                                                          nyl)-4-(2-thienyl)-2-                                                                      186                                                                pyrimidinamine                                      344  Ex. 26  [2-[bis(1-methyl-                                                                            N--[2-[2-[bis(1-                                                                           54-                                                  ethyl)amino[ethoxy                                                                           methylethyl)                                                                               57                                                   [guanidine hydro-                                                                            amino]ethoxy]                                                    chloride      phenyl]-4-(3-pyri-                                                             dinyl)-2-pyrimidi-                                                             namine                                              ______________________________________                                    

The disease diabetes mellitus is characterized by metabolic defects in the production and utilization of glucose which results in the failure to maintain appropriate blood sugar levels. The result of this defect is elevated blood glucose or hyperglycemia. Research on the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Treatments have included parenteral administration of exogenous insulin, oral administration of drugs and dietary therapies.

Two major forms of diabetes mellitus are now recognized. Type I diabetes, or insulin-dependent diabetes, is a result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. Type II diabetes, or insulin-independent diabetes, often occurs in the face of normal, or even elevated, levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin.

The compounds of the present invention and the pharmacologically active acid-addition salts thereof, effectively lower blood glucose levels when administered orally to genetic strains of hyperglycemic mice which are animal models of type II diabetes. The exact mechanism by which they act is not known and the invention should not be construed as limited to any particular mechanism of action. As effective hypoglycemic agents, these compounds are useful for the treatment of hyperglycemia in type II diabetes.

The compounds of this invention were tested for hypoglycemic activity according to the following procedure.

Obese mice [C57 B1/6J (ob/ob)], their lean littermates (ob/+ or +/+) and diabetic mice [C57 B1/Ks (db/db)] and their non-diabetic littermates (db/+ or +/+) were obtained from Jackson Laboratories, Bar Harbor, Maine. Obese mice were 8 weeks of age and diabetic mice were 9 weeks of age at the start of the test.

The test compounds were dissolved in methanol, mixed with powdered Purina rodent chow on a weight of compound to weight of chow basis and thoroughly dried.

Groups of 4 control mice received vehicle (methanol) treated chow.

Groups of 4 test mice were fed ad libitum for one month and food consumption was measured daily (on week days) by weighing the food bins before and after the addition of fresh chow. Thus a 40 g mouse fed the test compound at a concentration of 0.02% of the diet would receive a dose of 20 mg/kg/day if it ate 4 g of chow per day.

Blood samples were collected before the first treatment and once at the end of each week of treatment by retro-orbital puncture using the end of each week of treatment by retro-orbital puncture using herparinized capillary tubes. Plasma was separated by centrifugation in a Beckman microfuge for 5 minutes. Plasma glucose concentrations were determined with the Beckman Glucose Analyzer which uses a glucose oxidase method.

The results of this test on representative compounds of this invention appear in Table X.

                                      TABLE X                                      __________________________________________________________________________     Effect of Test Compounds on Blood Glucose                                                       Type                                                                               Dose                                                                               Blood Glucose Levels in mg/100 ml                                      of  %   Days                                                  COMPOUND         Mice                                                                               (W/W)                                                                              0  5  7  14 21 28                                     __________________________________________________________________________      --N--(4-methylphenyl)-4-(4-                                                                    ob/ob                                                                              0.1 219                                                                               137                                                pyridinyl)-2-pyrimidinamine                                                                     ob/ob                                                                              0.1 210   118                                                                                80                                                           ob/ob                                                                              0.025                                                                              209   223                                                                               166                                           --N--(4-Chlorophenyl)-4-(2-                                                                    ob/ob                                                                              0.1 212                                                                               160                                                thienyl)-2-pyrimidinanine                                                                       ob/ob                                                                              0.025                                                                              220   148                                                                               134                                           --N--(4-ethylphenyl) -4-(4-                                                                    ob/ob                                                                              0.1 216                                                                               181                                                pyridinyl)-2-pyrimidinamine                                                                     ob/ob                                                                              0.1 223                                                                               164                                                4-(2-furanyl)- --N--phenyl-2-                                                                   ob/ob                                                                              0.1 214                                                                               166                                                pyrimidinamine                                                                  --N--[4-(1,1-Dimethylethyl)                                                                    ob/ob                                                                              0.1 208                                                                               114                                                                               175                                             phenyl]-4-(3-pyridinyl)-2-                                                                      ob/ob                                                                              0.1 214                                                                               169                                                                               155                                             pyrimidinamine   ob/ob                                                                              0.1 218                                                                               124                                                                 ob/ob                                                                              0.1 229                                                                               118                                                                 ob/ob                                                                              0.1 225   120                                                                               116                                                                               131                                                                               135                                                     ob/ob                                                                              0.05                                                                               214   139                                                                               143                                                                               180                                                                               188                                                     ob/ob                                                                              0.01                                                                               214   163                                                                               138                                                                               181                                                                               162                                                     db/db                                                                              0.1 426   390                                                                               174                                                                               281                                                                               207                                                     db/db                                                                              0.05                                                                               429   314                                                                               293                                                                               250                                                                               270                                                     db/db                                                                              0.01                                                                               431   335                                                                               407                                                                               400                                                                               499                                     --N--[4-(Dimethylamino)phenyl]-                                                                ob/ob                                                                              0.1 240                                                                               138                                                4-(4-pyridinyl)-2-                                                                              ob/ob                                                                              0.1 230                                                                               147                                                pyrimidinamine                                                                  --N--[4-[3-(Dimethylamino)propoxy]                                                             ob/ob                                                                              0.1 215                                                                               234                                                phenyl]-4-(3-pyridinyl)-2-                                                     pyrimidinamine                                                                  --N--[4-[2-Diethylamino)ethoxy]                                                                ob/ob                                                                              0.1 220                                                                               191                                                phenyl]-4-(3-pyridinyl)-2-                                                     pyrimidinamine                                                                  --N'--[4-(2-Benzofurnayl)-2-                                                                   ob/ob                                                                              0.1 229                                                                               153                                                pyrimidinyl)- --N, --N--dimethyl-                                                               ob/ob                                                                              0.1 202                                                                               147                                                1,4-benzenediamine                                                                              ob/ob                                                                              0.1 223                                                                               144                                                 --N--[4-[2-(Dimethylam-                                                                        ob/ob                                                                              0.1 218                                                                               151                                                                               167                                             ino)ethoxy]phenyl]-4-                                                                           ob/ob                                                                              0.1 228                                                                               144                                                (4-pyridinyl)-2- ob/ob                                                                              0.1 225                                                                               134                                                pyrimidinamine   ob/ob                                                                              0.1 232   148                                                                               128                                                                               155                                                                               140                                                     ob/ob                                                                              0.05                                                                               230   158                                                                               198                                                                               196                                                                               163                                                     ob/ob                                                                              0.01                                                                               236   163                                                                               252                                                                               175                                                                               177                                                     db/db                                                                              0.1 369   410                                                                               403                                                                               328                                                                               222                                                     db/db                                                                              0.05                                                                               400   277                                                                               404                                                                               329                                                                               250                                                     db/db                                                                              0.01                                                                               368   393                                                                               321                                                                               494                                                                               336                                     --N--[4-(1 --H--Imidazol-1-                                                                    db/db                                                                              0.1 424   397                                                                               233                                          yl)phenyl]4-(4-pyri-                                                                            ob/ob                                                                              0.1 219                                                                               128                                                dinyl)-2-pyrimidin-                                                                             ob/ob                                                                              0.025                                                                              210   200                                                                               148                                          amine            ob/ob                                                                              0.1 211   105                                                                               140                                                           ob/ob                                                                              0.1 222   119                                                                               132                                                           ob/ob                                                                              0.01                                                                               219   158                                                                               159                                                           ob/ob                                                                              0.025                                                                              222   157                                                                               175                                           --N,N--Diethyl- --N.sup.1 --]4-                                                                ob/ob                                                                              0.1 223                                                                               138                                                (3-pyridinyl)-2-pyrim-                                                                          ob/ob                                                                              0.1 210                                                                               163                                                idinyl]-1,4-benzene-                                                                            ob/ob                                                                              0.1 216                                                                               153                                                diamine                                                                         --N--[4-(1H--Imidazol-                                                                         ob/ob                                                                              0.1 225                                                                               128                                                1-yl)phenyl]-4-(3-                                                                              ob/ob                                                                              0.025                                                                              208   159                                                                               171                                          pyridinyl)-2-pyrim-                                                                             ob/ob                                                                              0.1 218   127                                                                               131                                          idinamine                                                                       --N--[4-(1 --H--Imidazol-                                                                      ob/ob                                                                              0.1 217                                                                               171                                                1-yl)phenyl]-4-(2-                                                                              ob/ob                                                                              0.1 223                                                                               167                                                pyridinyl)-2-pyrimid-                                                                           ob/ob                                                                              0.1 234                                                                               141                                                inamine                                                                        4-(2-Furnayl)- --N--[4-                                                                         ob/ob                                                                              0.1 227                                                                               137                                                (1 --H--imidazol-1-yl)                                                                          ob/ob                                                                              0.025                                                                              215   164                                                                               244                                          phenyl]-2-pyrimidin-                                                                            ob/ob                                                                              0.1 214   140                                                                               160                                          amine                                                                           --N--[4-(1 --H--Imidazol-                                                                      ob/ob                                                                              0.1 221   109                                                                               116                                          1-yl)phenyl]-4-(2-                                                                              ob/ob                                                                              0.025                                                                              221   147                                                                               171                                          thienyl)-2-pyrimid-                                                                             ob/ob                                                                              0.01                                                                               217   212                                                                               161                                          inamine          ob/ob                                                                              0.1 224                                                                               125                                                                 ob/ob                                                                              0.1 203                                                                               131                                                                 ob/ob                                                                              0.1 231                                                                               126                                                                 ob/ob                                                                              0.1 218                                                                               134                                                                 ob/ob                                                                              0.025                                                                              218   175                                                                               185                                                           ob/ob                                                                              0.1 220   135                                                                               117                                                           db/db                                                                              0.1 423   492                                                                               349                                          4-[[4-(3-Pyridinyl)-                                                                            ob/ob                                                                              0.1 219                                                                               122                                                2-pyrimidinyl]amino]                                                                            ob/ob                                                                              0.1 240                                                                               147                                                benzenesulfonamide                                                                              ob/ob                                                                              0.1 216                                                                               185                                                                 ob/ob                                                                              0.1 229                                                                               142                                                                 ob/ob                                                                              0.1 228                                                                               211                                                 --N--(3-chlorophenyl)-4-                                                                       ob/ob                                                                              0.1 220                                                                               127                                                (4-pyrindinyl-2- ob/ob                                                                              0.1 237                                                                               163                                                pyrimidinamine   ob/ob                                                                              0.1 216                                                                               135                                                                 ob/ob                                                                              1.0 205                                                                               157                                                                 ob/ob                                                                              0.025                                                                              210   157                                                                               135                                                           ob/ob                                                                              0.1 212   173                                                                               129                                           --N--(3-Chlorophenyl)-                                                                         ob/ob                                                                              0.1 205                                                                               135                                                4-(3-pyridinyl)-2                                                                               ob/ob                                                                              0.025                                                                              221   205                                                                               131                                          pyrimidinamine   ob/ob                                                                              0.1 244   211                                                                               138                                           --N--[4-(4-Methyl-1-                                                                           ob/ob                                                                              0.1 212                                                                               236                                                piperazinyl)phenyl]-                                                           4-(3-pyridinyl)-2-                                                             pyrimidinamine                                                                  --N--(3-chlorophenyl)-                                                                         ob/ob                                                                              0.1 207                                                                               204                                                4-(2-pyridinyl)-2-                                                             pyrimidinamine                                                                 4-(2-Furnayl)- --N--[4-                                                                         ob/ob                                                                              0.1 203                                                                               149                                                (4-methyl-1-piper-                                                                              ob/ob                                                                              0.025                                                                              210   179                                                                               130                                          azinyl)phenyl]-2-                                                                               ob/ob                                                                              0.1 229   163                                                                               141                                          pyrimidinamine                                                                 4-(2-Furanyl)- --N--                                                                            ob/ob                                                                              0.1 221                                                                               132                                                (3-methoxyphenyl)-                                                                              ob/ob                                                                              0.1 239                                                                               113                                                2-pyrimidinamine ob/ob                                                                              0.1 217                                                                               162                                                                 ob/ob                                                                              0.1 219                                                                               209                                                 --N--[4-(4-Methyl-1-                                                                           ob/ob                                                                              0.1 203                                                                               188                                                piperazinyl)phenyl]-                                                           4-(2-thienyl)-2-                                                               pyrimidinamine                                                                  --N--[4-(4-Methyl-                                                                             ob/ob                                                                              0.1 204                                                                               210                                                1-piperazinyl)phenyl]-                                                         4-(2-pyridinyl)-2-                                                             pyrimidinamine                                                                  --N--[4-(4-Methyl-                                                                             ob/ob                                                                              0.1 204   118                                                                               124                                                                               178                                                                               161                                    1-piperazinyl)phenyl]-                                                                          ob/ob                                                                              0.025                                                                              210   157                                                                               200                                                                               152                                                                               202                                    4-(4-pyridinyl)-2-                                                                              ob/ob                                                                              0.01                                                                               210   130                                                                               192                                                                               178                                                                               147                                    pyrimidinamine   db/db                                                                              0.1 406   273                                                                               140                                                                               178                                                                               279                                                     ob/ob                                                                              0.1 221                                                                               125                                                                 ob/ob                                                                              0.1 233                                                                               131                                                                 ob/ob                                                                              0.1 226                                                                               117                                                                 ob/ob                                                                              0.1 215                                                                               138                                                                 ob/ob                                                                              0.025                                                                              231   154                                                                               134                                                           ob/ob                                                                              0.1 223   171                                                                               137                                           --N--[3-(1 --H--Imidazol-                                                                      ob/ob                                                                              0.1 225                                                                               173                                                1-yl)phenyl]-4-                                                                (3-pyridinyl)-2-                                                               pyrimidinamine                                                                  --N--[4-[2-(Diethylamino)                                                                      ob/ob                                                                              0.1 228                                                                               154                                                ethoxy]phenyl]-4-(2-                                                                            ob/ob                                                                              0.1 215                                                                               137                                                thienyl)-2-pyrimidinamine                                                       --N--[2-[2-[Bis(1-methyl-                                                                      ob/ob                                                                              0.1 228                                                                               153                                                ethyl)amino]ethoxy]                                                            phenyl]-4-(3-                                                                  pyridinyl)-2-pyrimid-                                                          inamine                                                                        __________________________________________________________________________ 

We claim:
 1. A compound selected from the group consisting of those of the formula: ##STR7## wherein R₁ is hydrogen, alkyl(C₁ -C₃), --COCO₂ C₂ H₅ or N,N-dimethylaminoethyl; R₂ is mono- or poly-substituted phenyl wherein the substituents are alkyl(C₁ -C₆), alkoxy(C₁ -C₃), chloro, bromo, iodo, trifluoromethyl, hydroxy, phenyl, amino, monoalkyl(C₁ -C₃)amino, dialkyl(C₁ -C₃)amino, alkyl(C₁ -C₃)keto, propenyloxy, carboxyl, oxyacetic acid, oxyacetic acid ethyl ester, sulfanilamido, N,N-dialkyl(C₁ -C₃)sulfanilamido, N-methylpiperazinyl, piperidinyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4-dimethylbenzyl or moieties of the formulae: ##STR8## wherein R is alkyl(C₁ -C₃), X is oxygen (--O--) or sulfur (--S--), m is 1-3, n is 2 or 3, R₆ is hydrogen, alkyl(C₁ -C₃), alkoxy (C₁ -C₃), chloro, bromo, iodo or trifluoromethyl, R₇ is 1H-imidazol-1-yl or morpholino and R₈ is alkyl(C₁ -C₃), phenyl or monosubstituted phenyl wherein the substituents are alkyl (C₁ -C₃), halogen or trifluoromethyl; R₃ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, 2-furanyl, 5-methyl-2-furanyl, 2,5-dimethyl-3-furanyl, 2-thienyl, 3-thienyl, 5-methyl-2-thienyl, 2-pheno-thiazinyl, 4-pyrazinyl, 2-benzofuranyl, 2-(pyridine-N-oxide), 3-(pyridine-N-oxide), 4-(pyridine-N-oxide), 1H-indol-2-yl, 1H-indol-3-yl, 1-methyl-1H-pyrrol-2-yl, 4-quinolinyl, 4-pyri-dinyl methyl iodide, dimethylaminophenyl or N-acetyl-N-methylaminophenyl; R₄ is hydrogen or alkyl(C₁ -C₃); and R₅ is hydrogen or alkyl(C₁ -C₃); and the pharmacologically acceptable acid-addition salts thereof.
 2. The compound according to claim 1; N-[3-(1H-imidazol-1-yl)phenyl]-4-(4-pyridinyl)-2-pyrimidinamine.
 3. The compound according to claim 1; N-[3-(1H-imidazol-1-yl)phenyl]-4-(2-pyridinyl)-2-pyrimidinamine.
 4. The compound according to claim 1; N,N-dimethyl-N'-[4-methyl-6-(4-pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine.
 5. The compound according to claim 1; N'-[4-(2-furanyl)-5-methyl-2-pyrimidinyl]-N,N-dimethyl-1,4-benzenediamine.
 6. The compound according to claim 1; N-[4-(dimethylamino)phenyl]-4-(4-pyridinyl)-2-pyrimidinamine.
 7. The compound according to claim 1; 4-(2-furanyl)-N-(3-methylphenyl)-2-pyrimidinamine.
 8. The compound according to claim 1; N,N-dimethyl-N'-[4-(4-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine, sulfate.
 9. The compound according to claim 1; N-[4-[2-(diethylamino)ethoxy]phenyl]-4-(4-pyridinyl)-2-pyrimidinamine.
 10. The compound according to claim 1; 4-(1H-indol-3-yl)-N-phenyl-2-pyrimidinamine.
 11. The compound according to claim 1; N-(4-ethylphenyl)-4-(4-pyridinyl)-2-pyrimidinamine.
 12. The compound according to claim 1; N,N-dimethyl-N'-[4-(3-pyridinyl)-2-pyrimidinyl]-1,4-benzenediamine, trihydrochloride.
 13. The compound according to claim 1; N-[4-(1H-imidazol-1-yl)phenyl]-4-(3-pyridinyl)-2-pyrimidinamine.
 14. The compound according to claim 1; N-[4-(4-methyl-1-piperazinyl)phenyl]-4-(3-pyridinyl)-2-pyrimidinamine.
 15. The compound according to claim 1; N-(3-methylphenyl)-4-(4-pyridinyl)-2-pyrimidinamine.
 16. A composition of matter in dosage unit form comprising from about 5 mg to about 1500 mg of a compound of claim 1 in association with a pharmaceutically acceptable carrier. 